Myst family histone acetyltransferase inhibitors

ABSTRACT

The present disclosure provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

SUMMARY

Protein acetylation is involved in several cellular processes. Lysineacetylation has been reported to modulate (e.g., inhibit) other proteinmodifications, such as methylation and ubiquitination, modify proteinstability, alter subcellular localization, or change the spectrum ofinteracting proteins.

Some aspects of the present disclosure are based on the recognition ofthe importance of histone acetyl transferases, such as lysine acetyltransferases (KATs), and in particular MYST family histoneacetyltransferases, in initiation and/or progression of some diseasesand disorders, e.g., in cancer.

Some aspects of the present disclosure encompass the recognition thatMYST family KATs represent a valuable target for modulating MYST familyKAT activity, e.g., KAT-5, KAT-6A, KAT-7, and/or KAT-8 activity, invitro and in vivo, including, for example, in a clinical context, suchas cancer therapies. Some aspects of the present disclosure provide thatMYST family KATs are therapeutic targets in diseases and conditionscharacterized by an aberrant activity of such KATs, e.g., an increasedKAT-5, KAT-6A, KAT-7, and/or KAT-8 activity as compared to therespective activity observed in healthy cells, tissues, or under normal,non-pathological conditions.

Some aspects of the present disclosure provide that MYST family KATs,e.g., KAT-5, KAT-6A, KAT-7, and/or KAT-8, are therapeutic targets invarious cancers. Some aspects of this disclosure are based on therecognition that MYST family KAT (e.g., KAT-5, KAT-6A, KAT-7, and/orKAT-8) activity in cancer cells is important for survival and/orproliferation of the cells. Some aspects of this disclosure providemethods and strategies for inhibiting the survival and/or proliferationof cells, e.g., of neoplastic or malignant cells, comprising contactingsuch cells with a MYST family KAT inhibitor, e.g., by contacting suchcells with an inhibitor that inhibits KAT-5, KAT-6A, KAT-7, or KAT-8, orany combination thereof, in vitro, or in vivo, e.g., by administeringthe inhibitor to a subject harboring such cells or a tumor comprisingsuch cells.

The present disclosure thus provides certain therapies useful for thetreatment of diseases or conditions characterized by aberrant MYSTfamily KAT (e.g., KAT-5, KAT-6A, KAT-7, and/or KAT-8) activity, such asvarious cancers. Methods and compositions provided by the presentdisclosure may be applicable, for example, to treatment of a wide rangeof solid tumors and/or to hematological malignancies.

Some aspects of this disclosure provide compounds, and pharmaceuticallyacceptable compositions thereof, that are inhibitors of MYST familylysine acetyl transferases (KATs). In some embodiments, the presentdisclosure provides inhibitors of MYST family KATs, e.g., of KAT-5,KAT-6A, KAT-7, and/or KAT-8. Such compounds have general formula I′:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,Z, R¹, R², R³, R^(a), and x with respect to formula I′ above, is asdefined and described in embodiments herein. Such compounds also havegeneral formula I:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,Z, R¹, R², R^(a), and x with respect to formula I above, is as definedand described in embodiments herein.

In some embodiments, compounds provided herein, and pharmaceuticallyacceptable compositions thereof, are useful for treating a variety ofdiseases, disorders, or conditions, characterized by, associated with,or mediated by KAT activity, e.g., by KAT-5, KAT-6A, KAT-7, and/or KAT-8activity. Such diseases, disorders, or conditions include thosedescribed herein.

Compounds provided by this disclosure are also useful for the study ofMYST family KATs in biological and pathological phenomena and thecomparative evaluation of new KAT inhibitors.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 presents a graph depicting the inhibition of acetylation of H3K23in the human cell line CAL-120 by compound A-30.

DEFINITIONS

Compounds of this disclosure include those described generally above,and are further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this disclosure, thechemical elements are identified in accordance with the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th)Ed. Additionally, general principles of organic chemistry are describedin “Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the disclosure. Unless otherwise stated, all tautomeric forms of thecompounds of the disclosure are within the scope of the disclosure.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this disclosure. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present disclosure.

Combinations of substituents and variables envisioned by this disclosureare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

Administration: As used herein, the term “administration” typicallyrefers to the administration of a composition to a subject or system.Those of ordinary skill in the art will be aware of a variety of routesthat may, in appropriate circumstances, be utilized for administrationto a subject, for example a human. For example, in some embodiments,administration may be systemic or local. In some embodiments,administration may be enteral or parenteral. In some embodiments,administration may be by injection (e.g., intramuscular, intravenous, orsubcutaneous injection). In some embodiments, injection may involvebolus injection, drip, perfusion, or infusion. In some embodimentsadministration may be topical. Those skilled in the art will be aware ofappropriate administration routes for use with particular therapiesdescribed herein, for example from among those listed on www.fda.gov,which include auricular (otic), buccal, conjunctival, cutaneous, dental,endocervical, endosinusial, endotracheal, enteral, epidural,extra-amniotic, extracorporeal, interstitial, intra-abdominal,intra-amniotic, intra-arterial, intra-articular, intrabiliary,intrabronchial, intrabursal, intracardiac, intracartilaginous,intracaudal, intracavernous, intracavitary, intracerebral,intracisternal, intracorneal, intracoronal, intracorporus cavernosum,intradermal, intradiscal, intraductal, intraduodenal, intradural,intraepidermal, intraesophageal, intragastic, intragingival,intralesional, intraluminal, intralymphatic, intramedullary,intrameningeal, intramuscular, intraocular, intraovarian,intrapericardial, intraperitoneal, intrapleural, intraprostatic,intrapulmonary, intrasinal, intraspinal, intrasynovial, intratendinous,intratesticular, intrathecal, intrathoracic, intratubular, intratumor,intratympanic, intrauterine, intravascular, intravenous, intravenousbolus, intravenous drip, intraventricular, intravitreal, laryngeal,nasal, nasogastric, ophthalmic, oral, oropharyngeal, parenteral,percutaneous, periarticular, peridural, perineural, periodontal, rectal,respiratory (e.g., inhalation), retrobulbar, soft tissue, subarachnoid,subconjunctival, subcutaneous, sublingual, submucosal, topical,transdermal, transmucosal, transplacental, transtracheal, ureteral,urethral, or vaginal. In some embodiments, administration may involveelectro-osmosis, hemodialysis, infiltration, iontophoresis, irrigation,and/or occlusive dressing. In some embodiments, administration mayinvolve dosing that is intermittent (e.g., a plurality of dosesseparated in time) and/or periodic (e.g., individual doses separated bya common period of time) dosing. In some embodiments, administration mayinvolve continuous dosing.

Agent. As used herein, the term “agent”, may refer to a compound,molecule, or entity of any chemical class including, for example, asmall molecule, polypeptide, nucleic acid, saccharide, lipid, metal, ora combination or complex thereof. In some embodiments, the term “agent”may refer to a compound, molecule, or entity that comprises a polymer.In some embodiments, the term may refer to a compound or entity thatcomprises one or more polymeric moieties. In some embodiments, the term“agent” may refer to a compound, molecule, or entity that issubstantially free of a particular polymer or polymeric moiety. In someembodiments, the term may refer to a compound, molecule, or entity thatlacks or is substantially free of any polymer or polymeric moiety.

Aliphatic: The term “aliphatic” or “aliphatic group”, as used herein,means a straight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “carbocyclic”, “cycloaliphatic” or“cycloalkyl”), that has a single point of attachment to the rest of themolecule. Unless otherwise specified, aliphatic groups contain 1-6aliphatic carbon atoms. In some embodiments, aliphatic groups contain1-5 aliphatic carbon atoms. In other embodiments, aliphatic groupscontain 1-4 aliphatic carbon atoms. In still other embodiments,aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet otherembodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. Insome embodiments, “carbocyclic” (or “cycloaliphatic” or “carbocycle” or“cycloalkyl”) refers to a monocyclic C₃-C₈ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic, that has a single point of attachment to therest of the molecule. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, or alkynyl groups and hybrids thereof such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

Alkylene: The term “alkylene” refers to a bivalent alkyl group.Exemplary alkylenes include —CH₂—, —CH₂CH₂—, —CH(CH₃)—, —CH₂CH(CH₃)—,—CH(CH₃)CH₂—, etc. In some embodiments, an “alkylene chain” is apolymethylene group, i.e., —(CH₂)_(n)—, wherein n is a positive integer,preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2to 3. A substituted alkylene chain is a bivalent alkyl group in whichone or more hydrogen atoms are replaced with a substituent. Suitablesubstituents include those described below for a substituted aliphaticgroup.

Allele: As used herein, the term “allele” refers to one of two or moreexisting genetic variants of a specific polymorphic genomic locus.

Amino acid: As used herein, the term “amino acid” refers to any compoundand/or substance that can be incorporated into a polypeptide chain,e.g., through formation of one or more peptide bonds. In someembodiments, an amino acid has the general structure H₂N—C(H)(R)—COOH.In some embodiments, an amino acid is a naturally-occurring amino acid.In some embodiments, an amino acid is a non-natural amino acid; in someembodiments, an amino acid is a D-amino acid; in some embodiments, anamino acid is an L-amino acid. As used herein, the term “standard aminoacid” refers to any of the twenty L-amino acids commonly found innaturally occurring peptides. “Nonstandard amino acid” refers to anyamino acid, other than the standard amino acids, regardless of whetherit is or can be found in a natural source. In some embodiments, an aminoacid, including a carboxy- and/or amino-terminal amino acid in apolypeptide, can contain a structural modification as compared to thegeneral structure above. For example, in some embodiments, an amino acidmay be modified by methylation, amidation, acetylation, pegylation,glycosylation, phosphorylation, and/or substitution (e.g., of the aminogroup, the carboxylic acid group, one or more protons, and/or thehydroxyl group) as compared to the general structure. In someembodiments, such modification may, for example, alter the stability orthe circulating half-life of a polypeptide containing the modified aminoacid as compared to one containing an otherwise identical unmodifiedamino acid. In some embodiments, such modification does notsignificantly alter a relevant activity of a polypeptide containing themodified amino acid, as compared to one containing an otherwiseidentical unmodified amino acid. As will be clear from context, in someembodiments, the term “amino acid” may be used to refer to a free aminoacid; in some embodiments it may be used to refer to an amino acidresidue of a polypeptide, e.g., an amino acid residue within apolypeptide.

Analog: As used herein, the term “analog” refers to a substance thatshares one or more particular structural features, elements, components,or moieties with a reference substance. Typically, an “analog” showssignificant structural similarity with the reference substance, forexample sharing a core or consensus structure, but also differs in oneor more certain discrete ways. In some embodiments, an analog is asubstance that can be generated from the reference substance, e.g., bychemical manipulation of the reference substance. In some embodiments,an analog is a substance that can be generated through performance of asynthetic process substantially similar to (e.g., sharing a plurality ofsteps with) one that generates the reference substance. In someembodiments, an analog can be generated through performance of asynthetic process different from that used to generate the referencesubstance.

Approximately: As used herein, the term “approximately” or “about,” asapplied to one or more values of interest, refers to a value that issimilar to a stated reference value. In certain embodiments, the term“approximately” or “about” refers to a range of values that fall within25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%,6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than orless than) of the stated reference value unless otherwise stated orotherwise evident from the context (for example when the one or morevalues of interest define a sufficiently narrow range that applicationof such a percentage variance would obviate the stated range).

Aryl: The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present disclosure, “aryl” refers to an aromatic ring system andexemplary groups include phenyl, biphenyl, naphthyl, anthracyl and thelike, which may bear one or more substituents. Also included within thescope of the term “aryl,” as it is used herein, is a group in which anaromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

Biological sample: The term “biological sample”, as used herein,includes, without limitation, cell cultures or extracts thereof;biopsied material obtained from a mammal or extracts thereof; and blood,saliva, urine, feces, semen, tears, or other body fluids or extractsthereof. Inhibition of activity of a lysine acetyl transferase, forexample, a MYST family KAT, such as, e.g., KAT-5, KAT-6A, KAT-7, and/orKAT-8, in a biological sample is useful for a variety of purposes thatare known to one of skill in the art. Examples of such purposes include,but are not limited to, blood transfusion, organ transplantation,biological specimen storage, and biological assays.

Bridged bicyclic: As used herein, the term “bridged bicyclic” refers toany bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated orpartially unsaturated, having at least one bridge. As defined by IUPAC,a “bridge” is an unbranched chain of atoms or an atom or a valence bondconnecting two bridgeheads, where a “bridgehead” is any skeletal atom ofthe ring system which is bonded to three or more skeletal atoms(excluding hydrogen). In some embodiments, a bridged bicyclic group has7-12 ring members and 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well knownin the art and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

Cancer: As used herein, the term “cancer” refers to a disease, disorder,or condition in which cells exhibit relatively abnormal, uncontrolled,and/or autonomous growth, so that they display an abnormally elevatedproliferation rate and/or aberrant growth phenotype characterized by asignificant loss of control of cell proliferation. In some embodiments,a cancer may be characterized by one or more tumors. Those skilled inthe art are aware of a variety of types of cancer including, forexample, adrenocortical carcinoma, astrocytoma, basal cell carcinoma,carcinoid, cardiac, cholangiocarcinoma, chordoma, chronicmyeloproliferative neoplasms, craniopharyngioma, ductal carcinoma insitu, ependymoma, intraocular melanoma, gastrointestinal carcinoidtumor, gastrointestinal stromal tumor (GIST), gestational trophoblasticdisease, glioma, histiocytosis, leukemia (e.g., acute lymphoblasticleukemia (ALL), acute myeloid leukemia (AML), chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CVIL), hairy cellleukemia, myelogenous leukemia, myeloid leukemia), lymphoma (e.g.,Burkitt lymphoma [non-Hodgkin lymphoma], cutaneous T-cell lymphoma,Hodgkin lymphoma, mycosis fungoides, Sezary syndrome, AIDS-relatedlymphoma, follicular lymphoma, diffuse large B-cell lymphoma), melanoma,merkel cell carcinoma, mesothelioma, myeloma (e.g., multiple myeloma),myelodysplastic syndrome, papillomatosis, paraganglioma,pheochromacytoma, pleuropulmonary blastoma, retinoblastoma, sarcoma(e.g., Ewing sarcoma, Kaposi sarcoma, osteosarcoma, rhabdomyosarcoma,uterine sarcoma, vascular sarcoma), Wilms' tumor, and/or cancer of theadrenal cortex, anus, appendix, bile duct, bladder, bone, brain, breast,bronchus, central nervous system, cervix, colon, endometrium, esophagus,eye, fallopian tube, gall bladder, gastrointestinal tract, germ cell,head and neck, heart, intestine, kidney (e.g., Wilms' tumor), larynx,liver, lung (e.g., non-small cell lung cancer, small cell lung cancer),mouth, nasal cavity, oral cavity, ovary, pancreas, rectum, skin,stomach, testes, throat, thyroid, penis, pharynx, peritoneum, pituitary,prostate, rectum, salivary gland, ureter, urethra, uterus, vagina, orvulva.

Chromosome: As used herein, the term “chromosome” refers to a DNAmolecule, optionally together with associated polypeptides and/or otherentities, for example as found in the nucleus of eukaryotic cells.Typically, a chromosome carries genes and functions (e.g., origin ofreplication) that permit it to transmit hereditary information.

Combination therapy: As used herein, the term “combination therapy”refers to a clinical intervention in which a subject is simultaneouslyexposed to two or more therapeutic regimens (e.g. two or moretherapeutic agents). In some embodiments, the two or more therapeuticregimens may be administered simultaneously. In some embodiments, thetwo or more therapeutic regimens may be administered sequentially (e.g.,a first regimen administered prior to administration of any doses of asecond regimen). In some embodiments, the two or more therapeuticregimens are administered in overlapping dosing regimens. In someembodiments, administration of combination therapy may involveadministration of one or more therapeutic agents or modalities to asubject receiving the other agent(s) or modality. In some embodiments,combination therapy does not necessarily require that individual agentsbe administered together in a single composition (or even necessarily atthe same time). In some embodiments, two or more therapeutic agents ormodalities of a combination therapy are administered to a subjectseparately, e.g., in separate compositions, via separate administrationroutes (e.g., one agent orally and another agent intravenously), and/orat different time points. In some embodiments, two or more therapeuticagents may be administered together in a combination composition, oreven in a combination compound (e.g., as part of a single chemicalcomplex or covalent entity), via the same administration route, and/orat the same time.

Corresponding to: As used herein in the context of polypeptides, nucleicacids, and chemical compounds, the term “corresponding to”, designatesthe position/identity of a structural element, e.g., of an amino acidresidue, a nucleotide residue, or a chemical moiety, in a compound orcomposition through comparison with an appropriate reference compound orcomposition.

Disease or disorder associated with a MYST family KAT: As used herein, a“disease or disorder associated with a MYST family KAT” or,alternatively, “a MYST family KAT-mediated disease or disorder” meansany disease or other deleterious condition in which a MYST family KAT(e.g., KAT-5, KAT-6A, KAT-7, or KAT-8), or a mutant of a MYST familyKAT, is known or suspected to play a role. For example, as used herein,a “disease or disorder associated with KAT-7” or, alternatively, “aKAT-7-mediated disease or disorder” means any disease or otherdeleterious condition in which KAT-7, or a mutant thereof, is known orsuspected to play a role.

Disease or disorder characterized by aberrant MYST-family KAT activity:As used herein, a “disease or disorder characterized by aberrant MYSTfamily KAT activity” means any disease or other deleterious condition inwhich an aberrant activity of a MYST family KAT (e.g., KAT-5, KAT-6A,KAT-7, or KAT-8), or a mutant thereof, is known or suspected to play arole. An aberrant activity includes, for example, an increased level ofa MYST family KAT (e.g., KAT-5, KAT-6A, KAT-7, and/or KAT-8) activity ascompared to a control or reference level. In some embodiments, thecontrol or reference level is an activity level of the MYST family KAT(e.g., KAT-5, KAT-6A, KAT-7, and/or KAT-8) observed, measured, orexpected in the absence of the disease or condition, e.g., in a normalcell, tissue, or sample. For example, as used herein, a “disease ordisorder characterized by aberrant KAT-7 activity” means any disease orother deleterious condition in which an aberrant activity of KAT-7, or amutant thereof, is known or suspected to play a role. An aberrantactivity includes, for example, an increased level of KAT-7 activity ascompared to a control or reference level. In some embodiments, thecontrol or reference level is an activity level of KAT-7 observed,measured, or expected in the absence of the disease or condition, e.g.,in a normal cell, tissue, or sample.

Domain: As used herein the term “domain” refers to a section or portionof a polypeptide. In some embodiments, a “domain” is associated with aparticular structural and/or functional feature of the polypeptide sothat, when the domain is physically separated from the rest of itsparent polypeptide, it substantially or entirely retains the particularstructural and/or functional feature. In some embodiments, a domain mayinclude a portion of a polypeptide that, when separated from that(parent) polypeptide and linked with a different (recipient)polypeptide, substantially retains and/or imparts on the recipientpolypeptide one or more structural and/or functional features thatcharacterized it in the parent polypeptide. In some embodiments, adomain is a section of a polypeptide. In some such embodiments, a domainis characterized by a particular structural element (e.g., a particularamino acid sequence or sequence motif, α-helix character, β-sheetcharacter, coiled-coil character, random coil character), and/or by aparticular functional feature (e.g., binding activity, enzymaticactivity, folding activity, or signaling activity).

Epigenetic Mark: As used herein, the term “epigenetic mark” refers to afeature of a nucleic acid or polypeptide not directly governed bygenetic code. For example, in some embodiments, an epigenetic mark mayrepresent or result from a modification to the nucleic acid orpolypeptide. In some embodiments, such modification can include, forexample, methylation, acetylation, ubiquitiniation, phosphorylation,ribosylation, amidation, glycosylation or combinations thereof.

Expression: As used herein, the term “expression” of a nucleic acidsequence refers to the generation of any gene product from the nucleicacid sequence. In some embodiments, a gene product can be a transcript.In some embodiments, a gene product can be a polypeptide. In someembodiments, expression of a nucleic acid sequence involves one or moreof the following: (1) production of an RNA template from a DNA sequence(e.g., by transcription); (2) processing of an RNA transcript (e.g., bysplicing, editing, 5′ cap formation, and/or 3′ end formation); (3)translation of an RNA into a polypeptide or protein; and/or (4)post-translational modification of a polypeptide or protein.

Gene: As used herein, the term “gene” refers to a DNA sequence in achromosome that encodes a gene product (e.g., an RNA product and/or apolypeptide product). In some embodiments, a gene includes a codingsequence (e.g., a sequence that encodes a particular gene product); insome embodiments, a gene includes a non-coding sequence. In someparticular embodiments, a gene may include both coding (e.g., exonic)and non-coding (e.g., intronic) sequences. In some embodiments, a genemay include one or more regulatory elements (e.g. promoters, enhancers,silencers, termination signals) that, for example, may control or impactone or more aspects of gene expression (e.g., cell-type-specificexpression, inducible expression).

Halogen: The term “halogen” means F, Cl, Br, or I.

Heteroaton: The term “heteroatom” means one or more of oxygen, sulfur,nitrogen, phosphorus, or silicon (including, any oxidized form ofnitrogen, sulfur, phosphorus, or silicon; the quaternized form of anybasic nitrogen; or a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

Heteroaryl: The terms “heteroaryl” and “heteroar-,” used alone or aspart of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,”refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ringatoms; having 6, 10, or 14 π electrons shared in a cyclic array; andhaving, in addition to carbon atoms, from one to five heteroatoms. Theterm “heteroatom” refers to nitrogen, oxygen, or sulfur, and includesany oxidized form of nitrogen or sulfur, and any quaternized form of abasic nitrogen. Exemplary heteroaryl groups include thienyl, furanyl,pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”,as used herein, also include groups in which a heteroaromatic ring isfused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherethe radical or point of attachment is on the heteroaromatic ring.Exemplary groups include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

Heterocycle: As used herein, the terms “heterocycle,” “heterocyclyl,”“heterocyclic radical,” and “heterocyclic ring” are used interchangeablyand refer to a stable 5- to 7-membered monocyclic or 7- to 10-memberedbicyclic heterocyclic moiety that is either saturated or partiallyunsaturated, and having, in addition to carbon atoms, one or more,preferably one to four, heteroatoms, as defined above. When used inreference to a ring atom of a heterocycle, the term “nitrogen” includesa substituted nitrogen. As an example, in a saturated or partiallyunsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur ornitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl-

NH (as in pyrrolidinyl-

NR^({circumflex over ( )}) (as in N-substituted 2-pyrrolidinyl-

or ⁺NR^({circumflex over ( )}) (as in N-substituted 1-pyrrolidinyl-

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals includetetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl,pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, isoindolinyl, chromanyl, phenanthridinyl,or tetrahydroquinolinyl, where the radical or point of attachment is onthe heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic.The term “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

Inhibitor: As used herein, the term “inhibitor” is defined as a compoundthat binds to and/or inhibits a target protein, here a MYST family KAT,e.g., KAT-5, KAT-6A, KAT-7, and/or KAT-8, with measurable affinity. Incertain embodiments, an inhibitor has an IC₅₀ and/or binding constant ofless than about 50 μM, less than about 1 μM, less than about 500 nM,less than about 100 nM, or less than about 10 nM.

Lower alkyl: The term “lower alkyl” refers to a C₁₋₄ straight orbranched alkyl group. Exemplary lower alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, and tert-butyl.

Lower haloalkyl: The term “lower haloalkyl” refers to a C₁₋₄ straight orbranched alkyl group that is substituted with one or more halogen atoms.

Measurable affinity: The terms “measurable affinity” and “measurablyinhibit,” as used herein, means a measurable change in the activity of atarget enzyme, here a MYST family KAT, e.g., KAT-5, KAT-6A, KAT-7,and/or KAT-8 between a sample comprising compounds of the presentdisclosure, or compositions thereof, and the target enzyme, and anequivalent sample comprising the target enzyme in the absence of saidcompound, or composition thereof.

Mutant: As used herein, the term “mutant” refers to an organism, a cell,or a biomolecule (e.g., a nucleic acid or a protein) that comprises agenetic variation as compared to a reference organism, cell, orbiomolecule. For example, a mutant nucleic acid may, in someembodiments, comprise a mutation, e.g., a nucleobase substitution, adeletion of one or more nucleobases, an insertion of one or morenucleobases, an inversion of two or more nucleobases, or a truncation,as compared to a reference nucleic acid molecule. Similarly, a mutantprotein may comprise an amino acid substitution, insertion, inversion,or truncation, as compared to a reference polypeptide. Additionalmutations, e.g., fusions and indels, are known to those of skill in theart. An organism or cell comprising or expressing a mutant nucleic acidor polypeptide is also sometimes referred to herein as a “mutant.” Insome embodiments, a mutant comprises a genetic variant that isassociated with a loss of function of a gene product. A loss of functionmay be a complete abolishment of function, e.g., an abolishment of theenzymatic activity of an enzyme, or a partial loss of function, e.g., adiminished enzymatic activity of an enzyme. In some embodiments, amutant comprises a genetic variant that is associated with a gain offunction, e.g., with a negative or undesirable alteration in acharacteristic or activity in a gene product. In some embodiments, amutant is characterized by a reduction or loss in a desirable level oractivity as compared to a reference; in some embodiments, a mutant ischaracterized by an increase or gain of an undesirable level or activityas compared to a reference. In some embodiments, the reference organism,cell, or biomolecule is a wild-type organism, cell, or biomolecule.

Nucleic acid: As used herein, the term “nucleic acid” refers to apolymer of at least three nucleotides. In some embodiments, a nucleicacid comprises DNA. In some embodiments comprises RNA. In someembodiments, a nucleic acid is single stranded. In some embodiments, anucleic acid is double stranded. In some embodiments, a nucleic acidcomprises both single and double stranded portions. In some embodiments,a nucleic acid comprises a backbone that comprises one or morephosphodiester linkages. In some embodiments, a nucleic acid comprises abackbone that comprises both phosphodiester and non-phosphodiesterlinkages. For example, in some embodiments, a nucleic acid may comprisea backbone that comprises one or more phosphorothioate or5′-N-phosphoramidite linkages and/or one or more peptide bonds, e.g., asin a “peptide nucleic acid”. In some embodiments, a nucleic acidcomprises one or more, or all, natural residues (e.g., adenine,cytosine, deoxyadenosine, deoxycytidine, deoxyguanosine, deoxythymidine,guanine, thymine, uracil). In some embodiments, a nucleic acid comprisesone or more, or all, non-natural residues. In some embodiments, anon-natural residue comprises a nucleoside analog (e.g.,2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyladenosine, 5-methylcytidine, C-5 propynyl-cytidine, C-5propynyl-uridine, 2-aminoadenosine, C5-bromouridine, C5-fluorouridine,C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine,C5-methylcytidine, 2-aminoadenosine, 7-deazaadenosine, 7-deazaguanosine,8-oxoadenosine, 8-oxoguanosine, 0(6)-methylguanine, 2-thiocytidine,methylated bases, intercalated bases, and combinations thereof). In someembodiments, a non-natural residue comprises one or more modified sugars(e.g., 2′-fluororibose, ribose, 2′-deoxyribose, arabinose, and hexose)as compared to those in natural residues. In some embodiments, a nucleicacid has a nucleotide sequence that encodes a functional gene productsuch as an RNA or polypeptide. In some embodiments, a nucleic acid has anucleotide sequence that comprises one or more introns. In someembodiments, a nucleic acid may be prepared by isolation from a naturalsource, enzymatic synthesis (e.g., by polymerization based on acomplementary template, e.g., in vivo or in vitro, reproduction in arecombinant cell or system, or chemical synthesis. In some embodiments,a nucleic acid is at least 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35,40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140,150, 160, 170, 180, 190, 20, 225, 250, 275, 300, 325, 350, 375, 400,425, 450, 475, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000,3500, 4000, 4500, 5000 or more residues long.

Parenteral: The term “parenteral” as used herein includes subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques.

Partially unsaturated: As used herein, the term “partially unsaturated”refers to a ring moiety that includes at least one double or triplebond. The term “partially unsaturated” is intended to encompass ringshaving multiple sites of unsaturation, but is not intended to includearyl or heteroaryl moieties, as herein defined.

Peptide: As used herein, the term “peptide” refers to a polypeptide thatis typically relatively short, for example having a length of less thanabout 100 amino acids, less than about 50 amino acids, less than about40 amino acids less than about 30 amino acids, less than about 25 aminoacids, less than about 20 amino acids, less than about 15 amino acids,or less than 10 amino acids.

Pharmaceutical composition: As used herein, the term “pharmaceuticalcomposition” refers to a composition that is suitable for administrationto a human or animal subject. In some embodiments, a pharmaceuticalcomposition comprises an active agent formulated together with one ormore pharmaceutically acceptable carriers. In some embodiments, theactive agent is present in a unit dose amount appropriate foradministration in a therapeutic regimen. In some embodiments, atherapeutic regimen comprises one or more doses administered accordingto a schedule that has been determined to show a statisticallysignificant probability of achieving a desired therapeutic effect whenadministered to a subject or population in need thereof. In someembodiments, a pharmaceutical composition may be specially formulatedfor administration in solid or liquid form, including those adapted forthe following: oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets, e.g., those targeted forbuccal, sublingual, and systemic absorption, boluses, powders, granules,pastes for application to the tongue; parenteral administration, forexample, by subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; topical application, for example, as acream, ointment, or a controlled-release patch or spray applied to theskin, lungs, or oral cavity; intravaginally or intrarectally, forexample, as a pessary, cream, or foam; sublingually; ocularly;transdermally; or nasally, pulmonary, and to other mucosal surfaces. Insome embodiments, a pharmaceutical composition is intended and suitablefor administration to a human subject. In some embodiments, apharmaceutical composition is sterile and substantially pyrogen-free.

Pharmaceutically acceptable salt: As used herein, the term“pharmaceutically acceptable salt” refers to those salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. For example, S. M. Berge et al., describepharmaceutically acceptable salts in detail in J. PharmaceuticalSciences, 1977, 66, 1-19, incorporated herein by reference.Pharmaceutically acceptable salts of the compounds of this disclosureinclude those derived from suitable inorganic and organic acids andbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Pharmaceutically acceptable carrier, adjuvant, or vehicle: The term“pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to anon-toxic carrier, adjuvant, or vehicle that does not destroy thepharmacological activity of the compound with which it is formulated.Pharmaceutically acceptable carriers, adjuvants or vehicles that may beused in the compositions of this disclosure include, but are not limitedto, ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat. The amount of compounds of the presentdisclosure that may be combined with the carrier materials to produce acomposition in a single dosage form will vary depending upon the hosttreated, the particular mode of administration, etc. Preferably,provided compositions are formulated so that a dosage of between 0.01 toabout 100 mg/kg, or about 0.1 mg/kg to about 50 mg/kg, and preferablyfrom about 1 mg/kg to about 25 mg/kg, of subject body weight/day of theinhibitor can be administered to a patient receiving these compositionsto obtain the desired therapeutic effect. The amount of a compound ofthe present disclosure in the composition will also depend upon theparticular compound in the composition.

Polypeptide: As used herein, the term “polypeptide,” which isinterchangeably used herein with the term “protein,” refers to a polymerof at least three amino acid residues. In some embodiments, apolypeptide comprises one or more, or all, natural amino acids. In someembodiments, a polypeptide comprises one or more, or all non-naturalamino acids. In some embodiments, a polypeptide comprises one or more,or all, D-amino acids. In some embodiments, a polypeptide comprises oneor more, or all, L-amino acids. In some embodiments, a polypeptidecomprises one or more pendant groups or other modifications, e.g.,modifying or attached to one or more amino acid side chains, at thepolypeptide's N-terminus, at the polypeptide's C-terminus, or anycombination thereof. In some embodiments, a polypeptide comprises one ormore modifications such as acetylation, amidation, aminoethylation,biotinylation, carbamylation, carbonylation, citrullination,deamidation, deimination, eliminylation, glycosylation, lipidation,methylation, pegylation, phosphorylation, sumoylation, or combinationsthereof. In some embodiments, a polypeptide may participate in one ormore intra- or inter-molecular disulfide bonds. In some embodiments, apolypeptide may be cyclic, and/or may comprise a cyclic portion. In someembodiments, a polypeptide is not cyclic and/or does not comprise anycyclic portion. In some embodiments, a polypeptide is linear. In someembodiments, a polypeptide may comprise a stapled polypeptide. In someembodiments, a polypeptide participates in non-covalent complexformation by non-covalent or covalent association with one or more otherpolypeptides (e.g., as in an antibody). In some embodiments, apolypeptide has an amino acid sequence that occurs in nature. In someembodiments, a polypeptide has an amino acid sequence that does notoccur in nature. In some embodiments, a polypeptide has an amino acidsequence that is engineered in that it is designed and/or producedthrough action of the hand of man. In some embodiments, the term“polypeptide” may be appended to a name of a reference polypeptide,activity, or structure; in such instances it is used herein to refer topolypeptides that share the relevant activity or structure and thus canbe considered to be members of the same class or family of polypeptides.For each such class, the present specification provides and/or thoseskilled in the art will be aware of exemplary polypeptides within theclass whose amino acid sequences and/or functions are known; in someembodiments, such exemplary polypeptides are reference polypeptides forthe polypeptide class or family. In some embodiments, a member of apolypeptide class or family shows significant sequence homology oridentity with, shares a common sequence motif (e.g., a characteristicsequence element) with, and/or shares a common activity (in someembodiments at a comparable level or within a designated range) with areference polypeptide of the class; in some embodiments with allpolypeptides within the class). For example, in some embodiments, amember polypeptide shows an overall degree of sequence homology oridentity with a reference polypeptide that is at least about 30-40%, andis often greater than about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, 99% or more and/or includes at least one region(e.g., a conserved region that may in some embodiments comprise acharacteristic sequence element) that shows very high sequence identity,often greater than 90% or even 95%, 96%, 97%, 98%, or 99%. Such aconserved region usually encompasses at least 3-4 and often up to 20 ormore amino acids; in some embodiments, a conserved region encompasses atleast one stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15 or more contiguous amino acids. In some embodiments, a usefulpolypeptide may comprise a fragment of a parent polypeptide. In someembodiments, a useful polypeptide as may comprise a plurality offragments, each of which is found in the same parent polypeptide in adifferent spatial arrangement relative to one another than is found inthe polypeptide of interest (e.g., fragments that are directly linked inthe parent may be spatially separated in the polypeptide of interest orvice versa, and/or fragments may be present in a different order in thepolypeptide of interest than in the parent), so that the polypeptide ofinterest is a derivative of its parent polypeptide.

Reference: As used herein, the term “reference” refers to a standard orcontrol relative to which a comparison is performed. For example, insome embodiments, an agent, animal, individual, population, sample,sequence, or value of interest is compared to a reference or controlagent, animal, individual, population, sample, sequence, or value. Insome embodiments, a reference or control is tested and/or determinedsubstantially simultaneously with the testing or determination ofinterest. In some embodiments, a reference or control is a historicalreference or control, optionally embodied in a tangible medium.Typically, as would be understood by those skilled in the art, areference or control is determined or characterized under comparableconditions or circumstances to those under assessment. Those skilled inthe art will appreciate when sufficient similarities are present tojustify reliance on and/or comparison to a particular possible referenceor control.

Sample: As used herein, the term “sample” refers to a biological sampleobtained or derived from a source of interest, as described herein. Insome embodiments, a source of interest comprises an organism, such as amicrobe, a plant, an animal or a human. In some embodiments, abiological sample comprises biological tissue or fluid. In someembodiments, a biological sample may comprise bone marrow; blood; bloodcells; ascites; tissue or fine needle biopsy samples; cell-containingbody fluids; free floating nucleic acids; sputum; saliva; urine;cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph;gynecological fluids; skin swabs; vaginal swabs; oral swabs; nasalswabs; washings or lavages such as a ductal lavages or broncheoalveolarlavages; aspirates; scrapings; bone marrow specimens; tissue biopsyspecimens; surgical specimens; other body fluids, secretions, and/orexcretions; and/or cells therefrom. In some embodiments, a biologicalsample comprises cells obtained from an individual, e.g., from a humanor animal subject. In some embodiments, obtained cells are or includecells from an individual from whom the sample is obtained. In someembodiments, a sample is a “primary sample” obtained directly from asource of interest by any appropriate means. For example, in someembodiments, a primary biological sample is obtained by methods selectedfrom the group consisting of biopsy (e.g., fine needle aspiration ortissue biopsy), surgery, collection of body fluid (e.g., blood, lymph,feces). In some embodiments, as will be clear from context, the term“sample” refers to a preparation that is obtained by processing (e.g.,by removing one or more components of and/or by adding one or moreagents to) a primary sample. For example, filtering using asemi-permeable membrane. Such a “processed sample” may comprise, forexample nucleic acids or polypeptides extracted from a sample orobtained by subjecting a primary sample to techniques such asamplification or reverse transcription of mRNA, isolation and/orpurification of certain components.

Subject: As used herein, the term “subject” refers to an organism, forexample, a mammal (e.g., a human, a non-human mammal, a non-humanprimate, a primate, a laboratory animal, a mouse, a rat, a hamster, agerbil, a cat, or a dog). In some embodiments a human subject is anadult, adolescent, or pediatric subject. In some embodiments, a subjectis suffering from a disease, disorder or condition, e.g., a disease,disorder or condition that can be treated as provided herein, e.g., acancer or a tumor listed herein. In some embodiments, a subject issusceptible to a disease, disorder, or condition; in some embodiments, asusceptible subject is predisposed to and/or shows an increased risk (ascompared to the average risk observed in a reference subject orpopulation) of developing the disease, disorder or condition. In someembodiments, a subject displays one or more symptoms of a disease,disorder or condition. In some embodiments, a subject does not display aparticular symptom (e.g., clinical manifestation of disease) orcharacteristic of a disease, disorder, or condition. In someembodiments, a subject does not display any symptom or characteristic ofa disease, disorder, or condition. In some embodiments, a subject is apatient. In some embodiments, a subject is an individual to whomdiagnosis and/or therapy is and/or has been administered.

Substituted or optionally substituted: As described herein, compounds ofthe disclosure may contain “optionally substituted” moieties. Ingeneral, the term “substituted,” whether preceded by the term“optionally” or not, means that one or more hydrogens of the designatedmoiety are replaced with a suitable substituent. “Substituted” appliesto one or more hydrogens that are either explicit or implicit from thestructure (e.g.,

refers to at least

refers to at least

Unless otherwise indicated, an “optionally substituted” group may have asuitable substituent at each substitutable position of the group, andwhen more than one position in any given structure may be substitutedwith more than one substituent selected from a specified group, thesubstituent may be either the same or different at every position.Combinations of substituents envisioned by this disclosure arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂, —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘) ₂;—C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 3-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a 3- to12-membered saturated, partially unsaturated, or aryl mono- or bicyclicring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂, —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), —SSR^(●), or -Ph which may besubstituted with R^(●), wherein each R^(●) is unsubstituted or wherepreceded by “halo” is substituted only with one or more halogens, and isindependently selected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a5- to 6-membered saturated, partially unsaturated, or aryl ring having0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.Suitable divalent substituents on a saturated carbon atom of R^(∘)include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O (“oxo”), ═S,═NNR*₂, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*,—O(C(R*₂))₂₋₃O—, or —S(C(R*₂))₂₋₃S—, wherein each independent occurrenceof R* is selected from hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, or an unsubstituted 5- to 6-membered saturated,partially unsaturated, or aryl ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. Suitable divalentsubstituents that are bound to vicinal substitutable carbons of an“optionally substituted” group include: —O(CR*₂)₂₋₃O—, wherein eachindependent occurrence of R* is selected from hydrogen, C₁₋₆ aliphaticwhich may be substituted as defined below, or an unsubstituted5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5- to 6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)NR^(†) ₂, —C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†),—S(O)₂NR^(†) ₂, —C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†);wherein each R^(†) is independently hydrogen, C₁₋₆ aliphatic which maybe substituted as defined below, unsubstituted —OPh, or an unsubstituted5- to 6-membered saturated, partially unsaturated, or aryl ring having0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,or, notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3- to 12-membered saturated, partially unsaturated, oraryl mono- or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5- to 6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Therapeutic agent: As used herein, the term “therapeutic agent” ingeneral refers to any agent that elicits a desired effect (e.g., adesired biological, clinical, or pharmacological effect) whenadministered to a subject. In some embodiments, an agent is consideredto be a therapeutic agent if it demonstrates a statistically significanteffect across an appropriate population. In some embodiments, anappropriate population is a population of subjects suffering from and/orsusceptible to a disease, disorder or condition. In some embodiments, anappropriate population is a population of model organisms. In someembodiments, an appropriate population may be defined by one or morecriterion such as age group, gender, genetic background, preexistingclinical conditions, or prior exposure to therapy. In some embodiments,a therapeutic agent is a substance that alleviates, ameliorates,relieves, inhibits, prevents, delays onset of, reduces severity of,and/or reduces incidence of one or more symptoms or features of adisease, disorder, and/or condition in a subject when administered tothe subject in an effective amount. In some embodiments, a “therapeuticagent” is an agent that has been or is required to be approved by agovernment agency before it can be marketed for administration tohumans. In some embodiments, a “therapeutic agent” is an agent for whicha medical prescription is required for administration to humans. In someembodiments, therapeutic agents may be MYST family KAT inhibitors, forexample, KAT-5, KAT-6A, KAT-7, and/or KAT-8 inhibitors, as describedherein.

Therapeutically effective amount: As used herein, the term“therapeutically effective amount” refers to an amount that produces adesired effect (e.g., a desired biological, clinical, or pharmacologicaleffect) in a subject or population to which it is administered. In someembodiments, the term refers to an amount statistically likely toachieve the desired effect when administered to a subject in accordancewith a particular dosing regimen (e.g., a therapeutic dosing regimen).In some embodiments, the term refers to an amount sufficient to producethe effect in at least a significant percentage (e.g., at least about25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%,about 90%, about 95%, or more) of a population that is suffering fromand/or susceptible to a disease, disorder, and/or condition. In someembodiments, a therapeutically effective amount is one that reduces theincidence and/or severity of, and/or delays onset of, one or moresymptoms of the disease, disorder, and/or condition. Those of ordinaryskill in the art will appreciate that the term “therapeuticallyeffective amount” does not in fact require successful treatment beachieved in a particular individual. Rather, a therapeutically effectiveamount may be an amount that provides a particular desired response in asignificant number of subjects when administered to patients in need ofsuch treatment, e.g., in at least about 25%, about 30%, about 40%, about50%, about 60%, about 70%, about 80%, about 90%, about 95%, or morepatients within a treated patient population. In some embodiments,reference to a therapeutically effective amount may be a reference to anamount sufficient to induce a desired effect as measured in one or morespecific tissues (e.g., a tissue affected by the disease, disorder orcondition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine).Those of ordinary skill in the art will appreciate that, in someembodiments, a therapeutically effective amount of a particular agent ortherapy may be formulated and/or administered in a single dose. In someembodiments, a therapeutically effective agent may be formulated and/oradministered in a plurality of doses, for example, as part of a dosingregimen.

Treat, treatment or treating: As used herein, the terms “treatment,”“treat,” and “treating” refer to partially or completely alleviating,inhibiting, delaying onset of, preventing, ameliorating and/or relievinga disorder or condition, or one or more symptoms of the disorder orcondition, as described herein. In some embodiments, treatment may beadministered after one or more symptoms have developed. In someembodiments, the term “treating” includes preventing or halting theprogression of a disease or disorder. In other embodiments, treatmentmay be administered in the absence of symptoms. For example, treatmentmay be administered to a susceptible individual prior to the onset ofsymptoms (e.g., in light of a history of symptoms and/or in light ofgenetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence. Thus, in some embodiments, the term “treating”includes preventing relapse or recurrence of a disease or disorder.

Tumor: As used herein, the term “tumor” refers to an abnormal growth ofcells or tissue. In some embodiments, a tumor may comprise cells thatare precancerous (e.g., benign), malignant, pre-metastatic, metastatic,and/or non-metastatic. In some embodiments, a tumor is associated with,or is a manifestation of, a cancer. In some embodiments, a tumor may bea disperse tumor or a liquid tumor. In some embodiments, a tumor may bea solid tumor.

Unit dosage form: The expression “unit dosage form” as used hereinrefers to a physically discrete unit of a provided compound and/orcompositions thereof appropriate for the subject to be treated. It willbe understood, however, that the total daily usage of the active agent(i.e., compounds and compositions of the present disclosure) will bedecided by the attending physician within the scope of sound medicaljudgment. The specific effective dose level for any particular subject(i.e., patient) or organism will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;activity of specific active agent employed; specific compositionemployed; age, body weight, general health, sex and diet of the subject;time of administration, route of administration, and rate of excretionof the specific active agent employed; duration of the treatment; andlike factors well known in the medical arts.

Unsaturated: The term “unsaturated,” as used herein, means that a moietyhas one or more units of unsaturation.

Wild-type: As used herein, the term “wild-type” refers to a form of anentity (e.g., a polypeptide or nucleic acid) that has a structure and/oractivity as found in nature in a “normal” (as contrasted with mutant,diseased, altered) state or context. In some embodiments, more than one“wild type” form of a particular polypeptide or nucleic acid may existin nature, for example as “alleles” of a particular gene or normalvariants of a particular polypeptide. In some embodiments, that form (orthose forms) of a particular polypeptide or nucleic acid that is mostcommonly observed in a population (e.g., in a human population) is the“wild type” form.

: As used herein, “

” represents a point of attachment between two atoms in a chemicalstructure.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

According to some aspects, the present disclosure provides a compound offormula I′:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   Z is selected from —Cy, —(C₁₋₃ aliphatic)-Cy, or optionally        substituted C₁₋₄ aliphatic;    -   Cy is an optionally substituted group selected from phenyl, a        3-10 membered saturated or partially unsaturated carbocyclic        ring, a 6-10 membered bridged bicyclic carbocyclic ring, a 3-10        membered saturated or partially unsaturated heterocyclic ring        having 1-2 heteroatoms independently selected from nitrogen,        oxygen and sulfur, a 6-8 membered bridged bicyclic heterocyclic        ring having 1-2 heteroatoms independently selected from        nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring        having 1-3 heteroatoms independently selected from nitrogen,        oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an        8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms        independently selected from nitrogen oxygen and sulfur;    -   each of R¹ and R² is independently selected from halogen and        C₁₋₄ aliphatic; R³ is selected from hydrogen, halogen, —CN,        —NR₂, and optionally substituted C₁₋₄ aliphatic; each R is        independently selected from hydrogen, optionally substituted        C₁₋₄ aliphatic, and —C(O)O(C₁₋₄ aliphatic);    -   Ring A is an optionally substituted 5- or 6-membered heteroaryl        ring having 1-4 heteroatoms independently selected from        nitrogen, oxygen and sulfur;    -   each R^(a) is selected from halogen and optionally substituted        C₁₋₄ aliphatic; and    -   x is 0-3.

According to some aspects, the present disclosure provides a compound offormula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   Z is selected from —Cy, —(C₁₋₃ aliphatic)-Cy or optionally        substituted C₁₋₄ aliphatic;    -   Cy is an optionally substituted group selected from phenyl, a        3-10 membered saturated or partially unsaturated carbocyclic        ring, a 3-10 membered saturated or partially unsaturated        heterocyclic ring having 1-2 heteroatoms independently selected        from nitrogen, oxygen and sulfur, a 6-8 membered bridged        bicyclic heterocyclic ring having 1-2 heteroatoms independently        selected from nitrogen, oxygen and sulfur, a 5-6 membered        heteroaryl ring having 1-3 heteroatoms independently selected        from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl        ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3        heteroatoms independently selected from nitrogen oxygen and        sulfur; each of R¹ and R² is independently selected from halogen        and C₁₋₄ aliphatic;    -   Ring A is an optionally substituted 5- or 6-membered heteroaryl        ring having 1-4 heteroatoms independently selected from        nitrogen, oxygen and sulfur;    -   each R^(a) is selected from halogen and optionally substituted        C₁₋₄ aliphatic; and    -   x is 0-3.

In some embodiments, the compound of formula I′ is not:

In some embodiments, the compound of formula I is not:

As defined above, Z is selected from —Cy, —(C₁₋₃ aliphatic)-Cy oroptionally substituted C₁₋₄ aliphatic.

In some embodiments, Z is optionally substituted C₁₋₄ aliphatic. In somesuch embodiments, Z is methyl, ethyl, isopropyl, and tert-butyl.

In some embodiments, Z is —Cy. In some such embodiments, Z is selectedfrom the group consisting of:

In some embodiments, Z is —Cy. In some such embodiments, Z is selectedfrom the group consisting of:

In some embodiments, Z is —Cy. In some such embodiments, Z is selectedfrom the group consisting of:

In some embodiments, Z is not:

In some embodiments, Z is —(C₁₋₃ aliphatic)-Cy. In some suchembodiments, Z is —CH₂-Cy. In some such embodiments, Z is selected fromthe group consisting of:

In some embodiments, Z is —(C₁₋₃ aliphatic)-Cy. In some suchembodiments, Z is —CH₂—Cy. In some such embodiments, Z is selected fromthe group consisting of:

As defined above, Cy is an optionally substituted group selected fromphenyl, a 3-10 membered saturated or partially unsaturated carbocyclicring, a 6-10 membered bridged bicyclic carbocyclic ring, a 3-10 memberedsaturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur, a6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur, a 5-6 memberedheteroaryl ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an8-10 membered bicyclic heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen oxygen and sulfur.

In some embodiments, Cy is phenyl.

In some embodiments, Cy is an optionally substituted 3-10 memberedsaturated or partially unsaturated carbocyclic ring. In someembodiments, Cy is an optionally substituted 3-10 membered saturatedcarbocyclic ring. In some such embodiments, Cy is an optionallysubstituted group selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cycloheptyl.

In some embodiments, Cy is an optionally substituted bicycliccarbocyclic ring. It will be appreciated that a bicyclic carbocyclicring can be a bridged bicyclic ring. In some such embodiments, Cy is anoptionally substituted group selected from:

In some such embodiments, Cy is an optionally substituted group selectedfrom:

In some such embodiments, Cy is an optionally substituted group selectedfrom:

In some embodiments, Cy is an optionally substituted 5-6 memberedheteroaryl ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen and sulfur. In some embodiments, Cy is a 5-memberedheteroaryl ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen and sulfur. In some such embodiments, Cy is anoptionally substituted group selected from pyrazolyl, imidazolyl, andtriazolyl. In some embodiments, Cy is an optionally substituted groupselected from:

In some embodiments, Cy is an optionally substituted group selectedfrom:

In some embodiments, Cy is an optionally substituted 5-6 memberedheteroaryl ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen and sulfur. In some embodiments, Cy is a 6-memberedheteroaryl ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen and sulfur. In some such embodiments, Cy is anoptionally substituted group selected from pyridinyl. In someembodiments, Cy is an optionally substituted group selected from:

In some embodiments, Cy is an optionally substituted group selectedfrom:

In some embodiments of formula I-a, Cy is an optionally substitutedgroup selected from:

In some embodiments, Cy is an optionally substituted 3-10 memberedsaturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, Cy is an optionally substituted 4-memberedsaturated heterocyclic group having 1 heteroatom independently selectedfrom nitrogen, oxygen and sulfur. In some such embodiments, Cy isoptionally substituted oxetanyl. In some such embodiments, Cy isoptionally substituted oxetanyl or azetidinyl.

In some embodiments, Cy is an optionally substituted 5-memberedsaturated heterocyclic group having 1-2 heteroatoms independentlyselected from nitrogen, oxygen and sulfur. In some such embodiments, Cyis an optionally substituted group selected from tetrahydrofuranyl andpyrrolidinyl.

In some embodiments, Cy is an optionally substituted 6-memberedsaturated heterocyclic group having 1-2 heteroatoms independentlyselected from nitrogen, oxygen and sulfur. In some such embodiments, Cyis an optionally substituted group selected from tetrahydropyranyl andpiperidinyl. In some such embodiments, Cy is an optionally substitutedgroup selected from tetrahydropyranyl, piperidinyl, and piperazinyl.

In some embodiments, Cy is an optionally substituted 7-memberedsaturated heterocyclic group having 1-2 heteroatoms independentlyselected from nitrogen, oxygen and sulfur. It will be appreciated that a7-membered saturated heterocyclic ring can be a bridged bicyclic ring.In some such embodiments, Cy is an optionally substituted group selectedfrom:

In some embodiments, Cy is an optionally substituted 8-memberedsaturated heterocyclic group having 1-2 heteroatoms independentlyselected from nitrogen, oxygen and sulfur. It will be appreciated thatan 8-membered saturated heterocyclic ring can be a bridged bicyclicring. In some such embodiments, Cy is an optionally substituted groupselected from:

As defined above, each of R¹ and R² is independently selected fromhalogen and C₁₋₄ aliphatic. In some embodiments, R¹ is fluoro. In someembodiments, R¹ is chloro. In some embodiments, R¹ is methyl. In someembodiments, R² is fluoro. In some embodiments, R² is chloro. In someembodiments, R² is methyl. In some embodiments, R¹ is fluoro and R² ischloro. In some embodiments, R¹ is fluoro and R² is methyl. In someembodiments, R¹ is fluoro and R² is fluoro. In some embodiments, R¹ ischloro and R² is chloro. In some embodiments, R¹ is methyl and R² ismethyl.

As defined above, R³ is selected from hydrogen, halogen, —CN, —NR₂, andoptionally substituted C₁₋₄ aliphatic. In some embodiments, R³ ishydrogen. In some embodiments, R³ is halogen. In some embodiments, R³ is—CN. In some embodiments, R³ is —NR₂. In some embodiments, R³ is —NH₂.In some embodiments, R³ is —N(C(O)O^(t)Bu)₂. In some embodiments, R³ isoptionally substituted C₁₋₄ aliphatic.

As defined above, each R is independently selected from hydrogen,optionally substituted C₁₋₄ aliphatic, and —C(O)O(C₁₋₄ aliphatic). Insome embodiments, each R is hydrogen. In some embodiments, each R is—C(O)O(C₁₋₄ aliphatic). In some embodiments, each R is —C(O)O^(t)Bu.

As defined above, Ring A is an optionally substituted 5- or 6-memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen and sulfur.

In some embodiments, Ring A is an optionally substituted 5-memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen and sulfur. In some embodiments, Ring A is anoptionally substituted 5-membered heteroaryl ring having 2-3 nitrogenatoms. In some such embodiments, Ring A is selected from pyrazolyl,imidazolyl, and triazolyl.

In some embodiments, Ring A is an optionally substituted 5-memberedheteroaryl ring having 4 nitrogen atoms. In some embodiments, Ring A istetrazol-5-yl.

In some embodiments, Ring A is an optionally substituted 5-memberedheteroaryl ring having 1 nitrogen atom and 1 additional heteroatomselected from oxygen and sulfur. In some such embodiments, Ring A isselected from oxazolyl and thiazolyl.

In some embodiments, Ring A is selected from:

In some embodiments, Ring A is selected from:

In some embodiments, Ring A is

In some embodiments, Ring A is not:

In some embodiments, Ring A is an optionally substituted 6-memberedheteroaryl ring having 1-4 heteroatoms independently selected nitrogen,oxygen and sulfur. In some such embodiments, Ring A is selected from2-pyridyl, 3-pyridyl and 4-pyridyl.

As defined above, x is 0-3. In some embodiments, x is 0. In someembodiments, x is 1. In some embodiments, x is 2. In some embodiments, xis 3. In some embodiments, x is 0-1. In some embodiments, x is 1-2.

In some embodiments,

is selected from the group consisting of:

In some embodiments,

In some embodiments, a compound of formula I is selected from the groupconsisting of those listed in Table 1:

Cmpd No Compound Structure I-1 

I-2 

I-3 

I-6 

I-7 

I-8 

I-4 

I-5 

I-11 

I-12 

I-13 

I-9 

I-10 

I-16 

I-17 

I-18 

I-14 

I-15 

I-21 

I-22 

I-23 

I-19 

I-20 

I-26 

I-27 

I-28 

I-24 

I-25 

I-31 

I-32 

I-33 

I-29 

I-30 

I-36 

I-37 

I-38 

I-34 

I-35 

I-41 

I-42 

I-43 

I-39 

I-40 

I-46 

I-47 

I-48 

I-44 

I-45 

I-51 

I-52 

I-53 

I-49 

I-50 

I-56 

I-57 

I-58 

I-54 

I-55 

I-61 

I-62 

I-63 

I-59 

I-60 

I-66 

I-67 

I-68 

I-64 

I-65 

I-71 

I-72 

I-73 

I-69 

I-70 

I-76 

I-77 

I-78 

I-74 

I-75 

I-81 

I-82 

I-83 

I-79 

I-80 

I-86 

I-87 

I-88 

I-84 

I-85 

I-91 

I-92 

I-93 

I-89 

I-90 

I-96 

I-97 

I-98 

I-94 

I-95 

I-101

I-102

I-103

I-99 

I-100

I-106

I-107

I-108

I-104

I-105

I-111

I-112

I-113

I-109

I-110

I-116

I-117

I-118

I-114

I-115

I-121

I-122

I-123

I-119

I-120

I-126

I-127

I-128

I-124

I-125

I-131

I-132

I-133

I-129

I-130

I-136

I-137

I-138

I-134

I-135

I-141

I-142

I-143

I-139

I-140

I-146

I-147

I-148

I-144

I-145

I-151

I-152

I-153

I-149

I-150

I-156

I-157

I-158

I-154

I-155

I-161

I-162

I-163

I-159

I-160

I-166

I-167

I-168

I-164

I-165

I-171

I-172

I-173

I-169

I-170

I-176

I-177

I-178

I-174

I-175

I-181

I-182

I-183

I-179

I-180

I-186

I-187

I-188

I-184

I-185

I-191

I-192

I-193

I-189

I-190

I-196

I-197

I-198

I-194

I-195

I-201

I-202

I-203

I-199

I-200

I-206

I-207

I-208

I-204

I-205

I-211

I-212

I-213

I-209

I-210

I-216

I-217

I-218

I-214

I-215

I-221

I-222

I-223

I-219

I-220

I-226

I-227

I-228

I-224

I-225

I-231

I-232

I-233

I-229

I-230

I-236

I-237

I-238

I-234

I-235

I-241

I-242

I-243

I-239

I-240

I-246

I-247

I-248

I-244

I-245

I-251

I-252

I-253

I-249

I-250

I-256

I-257

I-258

I-254

I-255

I-261

I-262

I-263

I-259

I-260

I-266

I-267

I-268

I-264

I-265

I-271

I-272

I-273

I-269

I-270

I-276

I-277

I-278

I-274

I-275

I-281

I-282

I-283

I-279

I-280

I-286

I-287

I-288

I-284

I-285

I-291

I-292

I-293

I-289

I-290

I-296

I-297

I-298

I-294

I-295

I-301

I-302

I-303

I-299

I-300

I-306

I-307

I-308

I-304

I-305

I-311

I-312

I-313

I-309

I-310

I-316

I-317

I-318

I-314

I-315

I-321

I-322

I-323

I-319

I-320

I-326

I-327

I-328

I-324

I-325

I-331

I-332

I-333

I-329

I-330

I-336

I-337

I-338

I-334

I-335

I-341

I-342

I-343

I-339

I-340

I-346

I-347

I-348

I-344

I-345

I-351

I-352

I-353

I-349

I-350

I-356

I-357

I-358

I-354

I-355

I-361

I-362

I-363

I-359

I-360

I-366

I-367

I-368

I-364

I-365

I-371

I-372

I-373

I-369

I-370

I-376

I-377

I-378

I-374

I-375

I-381

I-382

I-383

I-379

I-380

I-386

I-387

I-388

I-384

I-385

I-391

I-392

I-393

I-389

I-390

I-396

I-397

I-398

I-394

I-395

I-401

I-402

I-403

I-399

I-400

I-406

I-407

I-408

I-404

I-405

I-411

I-412

I-413

I-409

I-410

I-416

I-417

I-418

I-414

I-415

I-421

I-422

I-423

I-419

I-420

I-426

I-427

I-428

I-424

I-425

I-431

I-432

I-433

I-429

I-430

I-436

I-437

I-438

I-434

I-435

I-441

I-442

I-443

I-439

I-440

I-446

I-447

I-448

I-444

I-445

I-451

I-452

I-453

I-449

I-450

I-456

I-457

I-458

I-454

I-455

I-461

I-462

I-463

I-459

I-460

I-466

I-467

I-468

I-464

I-465

I-471

I-472

I-473

I-469

I-470

I-476

I-477

I-478

I-474

I-475

I-481

I-482

I-479

I-480

I-483

In some embodiments of formula I, R¹ is fluoro and R² is chloro, thusforming a compound of formula I-a:

or a pharmaceutically acceptable salt thereof, wherein each of Z, RingA, R^(a) and x is as defined above and described in classes andsubclasses herein.

As defined above, Z is selected from —Cy, —(C₁₋₃ aliphatic)-Cy oroptionally substituted C₁₋₄ aliphatic.

In some embodiments of formula I-a, Z is optionally substituted C₁₋₄aliphatic. In some such embodiments of formula I-a, Z is methyl, ethyl,isopropyl, and tert-butyl.

In some embodiments of formula I-a, Z is —Cy. In some such embodimentsof formula I-a, Z is selected from the group consisting of:

In some embodiments of formula I-a, Z is —Cy. In some such embodimentsof formula I-a, 2 is selected from the group consisting of:

In some embodiments, Z is —Cy. In some such embodiments, Z is selectedfrom the group consisting of:

In some embodiments of formula I-a, Z is not:

In some embodiments of formula I-a, Z is —(C₁₋₃ aliphatic)-Cy. In somesuch embodiments of formula I-a, Z is —CH₂—Cy. In some such embodimentsof formula I-a, Z is selected from the group consisting of:

In some embodiments, Z is —(C₁₋₃ aliphatic)-Cy. In some suchembodiments, Z is CH₂—Cy. In some such embodiments, Z is selected fromthe group consisting of:

As defined above, Cy is an optionally substituted group selected fromphenyl, a 3-10 membered saturated or partially unsaturated carbocyclicring, a 3-10 membered saturated or partially unsaturated heterocyclicring having 1-2 heteroatoms independently selected from nitrogen, oxygenand sulfur, a 6-8 membered bridged bicyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur, a5-6 membered heteroaryl ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclicaryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3heteroatoms independently selected from nitrogen oxygen and sulfur.

In some embodiments of formula I-a, Cy is phenyl.

In some embodiments of formula I-a, Cy is an optionally substituted 3-10membered saturated or partially unsaturated carbocyclic ring. In someembodiments, Cy is an optionally substituted 3-10 membered saturatedcarbocyclic ring. In some such embodiments, Cy is an optionallysubstituted group selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl.

In some embodiments of formula I-a, Cy is an optionally substitutedbicyclic carbocyclic ring. It will be appreciated that a bicycliccarbocyclic ring can be a bridged bicyclic ring. In some suchembodiments of formula I-a, Cy is an optionally substituted groupselected from:

In some such embodiments, Cy is an optionally substituted group selectedfrom:

In some such embodiments, Cy is an optionally substituted group selectedfrom:

In some embodiments of formula I-a, Cy is an optionally substituted 5-6membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. In some embodiments of formula I-a, Cyis a 5-membered heteroaryl ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen and sulfur. In some such embodiments offormula I-a, Cy is an optionally substituted group selected frompyrazolyl, imidazolyl, and triazolyl. In some embodiments of formulaI-a, Cy is an optionally substituted group selected from:

In some embodiments of formula I-a, Cy is an optionally substitutedgroup selected from:

In some embodiments of formula I-a, Cy is an optionally substituted 5-6membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. In some embodiments of formula I-a, Cyis a 6-membered heteroaryl ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen and sulfur. In some such embodiments offormula I-a, Cy is an optionally substituted group selected frompyridinyl. In some embodiments of formula I-a, Cy is an optionallysubstituted group selected from:

In some embodiments of formula I-a, Cy is an optionally substitutedgroup selected from:

In some embodiments of formula I-a, Cy is an optionally substituted 3-10membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments of formula I-a, Cy is an optionally substituted4-membered saturated heterocyclic group having 1 heteroatomindependently selected from nitrogen, oxygen and sulfur. In some suchembodiments of formula I-a, Cy is optionally substituted oxetanyl. Insome such embodiments, Cy is optionally substituted oxetanyl orazetidinyl.

In some embodiments of formula I-a, Cy is an optionally substituted5-membered saturated heterocyclic group having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur. In some suchembodiments of formula I-a, Cy is an optionally substituted groupselected from tetrahydrofuranyl and pyrrolidinyl.

In some embodiments of formula I-a, Cy is an optionally substituted6-membered saturated heterocyclic group having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur. In some suchembodiments of formula I-a, Cy is an optionally substituted groupselected from tetrahydropyranyl and piperidinyl. In some suchembodiments, Cy is an optionally substituted group selected fromtetrahydropyranyl, piperidinyl, and piperazinyl.

In some embodiments of formula I-a, Cy is an optionally substituted7-membered saturated heterocyclic group having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur. It will beappreciated that a 7-membered saturated heterocyclic ring can be abridged bicyclic ring. In some such embodiments of formula I-a, Cy is anoptionally substituted group selected from:

In some embodiments of formula I-a, Cy is an optionally substituted8-membered saturated heterocyclic group having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur. It will beappreciated that an 8-membered saturated heterocyclic ring can be abridged bicyclic ring. In some such embodiments of formula I-a, Cy is anoptionally substituted group selected from:

As defined above, each of R¹ and R² is independently selected fromhalogen and C₁₋₄ aliphatic. In some embodiments of formula I-a, R¹ isfluoro. In some embodiments of formula I-a, R¹ is chloro. In someembodiments of formula I-a, R¹ is methyl. In some embodiments of formulaI-a, R² is fluoro. In some embodiments of formula I-a, R² is chloro. Insome embodiments of formula I-a, R² is methyl. In some embodiments offormula I-a, R¹ is fluoro and R² is chloro. In some embodiments offormula I-a, R¹ is fluoro and R² is methyl. In some embodiments offormula I-a, R¹ is fluoro and R² is fluoro. In some embodiments offormula I-a, R¹ is chloro and R² is chloro. In some embodiments offormula I-a, R¹ is methyl and R² is methyl.

As defined above, Ring A is an optionally substituted 5- or 6-memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen and sulfur.

In some embodiments of formula I-a, Ring A is an optionally substituted5-membered heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. In some embodiments of formula I-a,Ring A is an optionally substituted 5-membered heteroaryl ring having2-3 nitrogen atoms. In some such embodiments of formula I-a, Ring A isselected from pyrazolyl, imidazolyl, and triazolyl.

In some embodiments of formula I, Ring A is an optionally substituted5-membered heteroaryl ring having 4 nitrogen atoms. In some embodimentsof formula I-a, Ring A is tetrazol-5-yl.

In some embodiments of formula I-a, Ring A is an optionally substituted5-membered heteroaryl ring having 1 nitrogen atom and 1 additionalheteroatom selected from oxygen and sulfur. In some such embodiments offormula I-a, Ring A is selected from oxazolyl and thiazolyl.

In some embodiments of formula I-a, Ring A is selected from:

In some embodiments of formula I-a, Ring A is selected from:

In some embodiments of formula I-a, Ring A is

In some embodiments of formula I-a, Ring A is an optionally substituted6-membered heteroaryl ring having 1-4 heteroatoms independently selectednitrogen, oxygen and sulfur. In some such embodiments of formula I-a,Ring A is selected from 2-pyridyl. 3-pyridyl and 4-pyridyl.

As defined above, x is 0-3. In some embodiments of formula I-a, x is 0.In some embodiments of formula I-a, x is 1. In some embodiments offormula I-a, x is 2. In some embodiments of formula I-a, x is 3. In someembodiments of formula I-a, x is 0-1. In some embodiments of formulaI-a, x is 1-2.

According to some aspects, the present disclosure provides a compound offormula II:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   Z is selected from —Cy, —(C₁₋₃ aliphatic)-Cy or optionally        substituted C₁₋₄ aliphatic;    -   Cy is an optionally substituted group selected from phenyl, a        3-10 membered saturated or partially unsaturated carbocyclic        ring, a 3-10 membered saturated or partially unsaturated        heterocyclic ring having 1-2 heteroatoms independently selected        from nitrogen, oxygen and sulfur, a 6-8 membered bridged        bicyclic heterocyclic ring having 1-2 heteroatoms independently        selected from nitrogen, oxygen and sulfur, a 5-6 membered        heteroaryl ring having 1-2 heteroatoms independently selected        from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl        ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3        heteroatoms independently selected from nitrogen oxygen and        sulfur;    -   each of R¹ and R² is independently selected from halogen and        C₁₋₄ aliphatic;    -   R^(x) is optionally substituted C₁₋₄ aliphatic; and    -   each of R^(a) and R^(a′) is independently selected from        hydrogen, halogen and optionally substituted C₁₋₄ aliphatic.

As defined above for formula II, Z is selected from —Cy, —(C₁₋₃aliphatic)-Cy or optionally substituted C₁₋₄ aliphatic.

As defined above for formula II, Cy is an optionally substituted groupselected from phenyl, a 3-10 membered saturated or partially unsaturatedcarbocyclic ring, a 3-10 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen and sulfur, a 6-8 membered bridged bicyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur, an8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclicheteroaryl ring having 1-3 heteroatoms independently selected fromnitrogen oxygen and sulfur.

As defined above for formula II, each of R¹ and R² is independentlyselected from halogen and C₁₋₄ aliphatic. In some embodiments of formulaII, R¹ is fluoro. In some embodiments of formula II, R¹ is chloro. Insome embodiments of formula II, R¹ is methyl. In some embodiments offormula II, R² is fluoro. In some embodiments of formula II, R² ischloro. In some embodiments of formula II, R² is methyl. In someembodiments of formula II, R¹ is fluoro and R² is chloro. In someembodiments of formula II, R¹ is fluoro and R² is methyl. In someembodiments of formula II, R¹ is fluoro and R² is fluoro. In someembodiments of formula II, R¹ is chloro and R² is chloro. In someembodiments, R¹ is methyl and R² is methyl.

As defined above for formula II, R^(x) is optionally substituted C₁₋₄aliphatic. In some embodiments of formula II, R^(x) is methyl. In someembodiments of formula II, R^(x) is ethyl. In some embodiments offormula II, R^(h) is isopropyl. In some embodiments of formula II, R^(x)is C₁₋₄ aliphatic optionally substituted with —(CH₂)₀₋₄OR^(∘), whereinR^(∘) is hydrogen or C₁₋₆ aliphatic.

As defined above for formula II, each of R^(a) and R^(a′) isindependently selected from hydrogen, halogen and optionally substitutedC₁₋₄ aliphatic. In some embodiments of formula II, R^(a) is hydrogen. Insome embodiments of formula II, R^(a) is optionally substituted C₁₋₄aliphatic. In some embodiments of formula II, R^(a) is C₁₋₄ aliphaticoptionally substituted with —(CH₂)₀₋₄ OR^(∘), wherein R^(∘) is hydrogenor C₁₋₆ aliphatic. In some such embodiments, R^(a) is —CH₂CH₂OCH₃. Insome embodiments of formula II, R^(a) is methyl. In some embodiments offormula II, R^(a) is halogen. In some such embodiments of formula II,R^(a) is chloro.

In some embodiments of formula II, R^(a) is hydrogen. In someembodiments of formula II, R^(a′) is methyl. In some embodiments offormula II, R^(a) is halogen. In some such embodiments of formula II,R^(a) is chloro.

As defined above for formula H, Z is selected from —Cy, —(C₁₋₃aliphatic)-Cy or optionally substituted C₁₋₄ aliphatic.

In some embodiments of formula II, Z is optionally substituted C₁₋₄aliphatic. In some such embodiments, Z is methyl, ethyl, isopropyl, andtert-butyl.

In some embodiments of formula II, Z is —Cy. In some such embodiments, Zis selected from the group consisting of:

In some embodiments of formula II, Z is —Cy. In some such embodiments, Zis selected from the group consisting of:

In some embodiments of formula II, Z is —Cy. In some such embodiments, Zis selected from the group consisting of:

In some embodiments of formula II, Z is —(C₁₋₃ aliphatic)-Cy. In somesuch embodiments, Z is —CH₂-Cy. In some such embodiments, Z is selectedfrom the group consisting of:

In some embodiments of formula II, Z is —(C₁₋₃ aliphatic)-Cy. In somesuch embodiments, Z is —CH₂—Cy. In some such embodiments, Z is selectedfrom the group consisting of:

As defined above for formula II, Cy is an optionally substituted groupselected from phenyl, a 3-10 membered saturated or partially unsaturatedcarbocyclic ring, a 3-10 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen and sulfur, a 6-8 membered bridged bicyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur, an8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclicheteroaryl ring having 1-3 heteroatoms independently selected fromnitrogen oxygen and sulfur.

In some embodiments of formula II, Cy is phenyl.

In some embodiments of formula II, Cy is an optionally substituted 3-10membered saturated or partially unsaturated carbocyclic ring. In someembodiments of formula II, Cy is an optionally substituted 3-10 memberedsaturated carbocyclic ring. In some such embodiments, Cy is anoptionally substituted group selected from cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

In some embodiments of formula II, Cy is an optionally substitutedbicyclic carbocyclic ring. It will be appreciated that a bicycliccarbocyclic ring can be a bridged bicyclic ring. In some suchembodiments, Cy is an optionally substituted group selected from:

In some such embodiments, Cy is an optionally substituted group selectedfrom:

In some such embodiments, Cy is an optionally substituted group selectedfrom:

In some embodiments of formula II, Cy is an optionally substituted 5-6membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. In some embodiments of formula II, Cyis a 5-membered heteroaryl ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen and sulfur. In some such embodiments, Cyis an optionally substituted group selected from pyrazolyl, imidazolyl,and triazolyl.

In some embodiments of formula II, Cy is selected from:

In some embodiments of formula II, Cy is an optionally substituted group

In some embodiments of formula II, Cy is an optionally substituted 5-6membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. In some embodiments, Cy is a6-membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. In some such embodiments, Cy is anoptionally substituted group selected from pyridinyl. In someembodiments, Cy is an optionally substituted group selected from:

In some embodiments of formula II, Cy is an optionally substituted groupselected from:

In some embodiments of formula II, Cy is an optionally substituted 3-10membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments of formula II, Cy is an optionally substituted4-membered saturated heterocyclic group having 1 heteroatomindependently selected from nitrogen, oxygen and sulfur. In some suchembodiments, Cy is optionally substituted oxetanyl. In some suchembodiments, Cy is optionally substituted oxetanyl or azetidinyl.

In some embodiments of formula II, Cy is an optionally substituted5-membered saturated heterocyclic group having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur. In some suchembodiments, Cy is an optionally substituted group selected fromtetrahydrofuranyl and pyrrolidinyl.

In some embodiments of formula II, Cy is an optionally substituted6-membered saturated heterocyclic group having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur. In some suchembodiments, Cy is an optionally substituted group selected fromtetrahydropyranyl and piperidinyl. In some such embodiments, Cy is anoptionally substituted group selected from tetrahydropyranyl,piperidinyl, and piperazinyl.

In some embodiments of formula II, Cy is an optionally substituted7-membered saturated heterocyclic group having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur. It will beappreciated that a 7-membered saturated heterocyclic ring can be abridged bicyclic ring. In some such embodiments, Cy is an optionallysubstituted group selected from:

In some embodiments of formula II, Cy is an optionally substituted8-membered saturated heterocyclic group having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur. It will beappreciated that an 8-membered saturated heterocyclic ring can be abridged bicyclic ring. In some such embodiments, Cy is an optionallysubstituted group selected from:

In some embodiments of formula II, R¹ is fluoro and R² is chloro, thusforming a compound of formula II-a:

or a pharmaceutically acceptable salt thereof, wherein each of Z, R^(x),R^(a) and x is as defined above and described in classes and subclassesherein.

In some embodiments of formula II, R¹ is fluoro, R² is chloro, and R^(Y)is methyl, thus forming a compound of formula II-b:

or a pharmaceutically acceptable salt thereof, wherein each of Z, R^(a)and R^(a′) is as defined above and described in classes and subclassesherein.

In some embodiments of formula TI, R¹ is fluoro, R² is chloro, R^(x) ismethyl, R^(a) is hydrogen and R^(a′) is hydrogen, thus forming acompound of formula II-c:

or a pharmaceutically acceptable salt thereof, wherein Z is as definedabove and described in classes and subclasses herein.

According to some aspects, the present disclosure provides a compound offormula III:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   Z is selected from —Cy, —(C₁₋₃ aliphatic)-Cy or optionally        substituted C₁₋₄ aliphatic;    -   Cy is an optionally substituted group selected from phenyl, a        3-10 membered saturated or partially unsaturated carbocyclic        ring, a 3-10 membered saturated or partially unsaturated        heterocyclic ring having 1-2 heteroatoms independently selected        from nitrogen, oxygen and sulfur, a 6-8 membered bridged        bicyclic heterocyclic ring having 1-2 heteroatoms independently        selected from nitrogen, oxygen and sulfur, and a 5-6 membered        heteroaryl ring having 1-2 heteroatoms independently selected        from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl        ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3        heteroatoms independently selected from nitrogen oxygen and        sulfur;    -   each of R¹ and R² is independently selected from halogen and        C₁₋₄ aliphatic; and    -   R^(x) is optionally substituted C₁₋₄ aliphatic.

As defined above for formula III, Z is selected from —Cy, —(C₁₋₃aliphatic)-Cy or optionally substituted C₁₋₄ aliphatic.

As defined above for formula III, Cy is an optionally substituted groupselected from phenyl, a 3-10 membered saturated or partially unsaturatedcarbocyclic ring, a 3-10 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen and sulfur, a 6-8 membered bridged bicyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur, an8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclicheteroaryl ring having 1-3 heteroatoms independently selected fromnitrogen oxygen and sulfur.

As defined above for formula III, each of R¹ and R² is independentlyselected from halogen and C₁₋₄ aliphatic. In some embodiments of formulaIII, R¹ is fluoro. In some embodiments of formula III, R¹ is chloro. Insome embodiments of formula III, R¹ is methyl. In some embodiments offormula III, R² is fluoro. In some embodiments of formula II, R² ischloro. In some embodiments of formula III, R² is methyl. In someembodiments of formula III, R¹ is fluoro and R² is chloro. In someembodiments of formula III, R¹ is fluoro and R² is methyl. In someembodiments of formula III, R¹ is fluoro and R² is fluoro. In someembodiments of formula III, R¹ is chloro and R² is chloro. In someembodiments, R¹ is methyl and R² is methyl.

As defined above for formula III, R^(x) is optionally substituted C₁₋₄aliphatic. In some embodiments of formula III, R^(x) is methyl. In someembodiments of formula III, R^(x) is ethyl. In some embodiments offormula III, R^(x) is isopropyl. In some embodiments of formula III,R^(x) is C₁₋₄ aliphatic optionally substituted with —(CH₂)₀₋₄OR^(∘),wherein R^(∘) is hydrogen or C₁₋₆ aliphatic.

As defined above for formula III, Z is selected from —Cy, —(C₁₋₃aliphatic)-Cy or optionally substituted C₁₋₄ aliphatic.

In some embodiments of formula III, Z is optionally substituted C₁₋₄aliphatic. In some such embodiments, Z is methyl, ethyl, isopropyl, andtert-butyl.

In some embodiments of formula III, Z is —Cy.

In some embodiments of formula III, Z is —(C₁₋₃ aliphatic)-Cy. In somesuch embodiments, Z is —CH₂—Cy. In some such embodiments, Z is selectedfrom the group consisting of:

In some embodiments of formula III, Z is —(C₁₋₃ aliphatic)-Cy. In somesuch embodiments, Z is —CH₂—Cy. In some such embodiments, Z is selectedfrom the group consisting of:

As defined above for formula III, Cy is an optionally substituted groupselected from phenyl, a 3-10 membered saturated or partially unsaturatedcarbocyclic ring, a 3-10 membered saturated or partially unsaturatedheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen and sulfur, a 6-8 membered bridged bicyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur, an8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclicheteroaryl ring having 1-3 heteroatoms independently selected fromnitrogen oxygen and sulfur.

In some embodiments of formula III, Cy is phenyl.

In some embodiments of formula III, Cy is an optionally substituted 3-10membered saturated or partially unsaturated carbocyclic ring. In someembodiments of formula III, Cy is an optionally substituted 3-10membered saturated carbocyclic ring. In some such embodiments, Cy is anoptionally substituted group selected from cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

In some embodiments of formula III, Cy is an optionally substitutedbicyclic carbocyclic ring. It will be appreciated that a bicycliccarbocyclic ring can be a bridged bicyclic ring. In some suchembodiments, Cy is an optionally substituted group selected from:

In some such embodiments, Cy is an optionally substituted group selectedfrom:

In some such embodiments, Cy is an optionally substituted group selectedfrom:

In some embodiments of formula III, Cy is an optionally substituted 5-6membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. In some embodiments of formula III, Cyis a 5-membered heteroaryl ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen and sulfur. In some such embodiments, Cyis an optionally substituted group selected from pyrazolyl, imidazolyl,and triazolyl.

In some embodiments of formula III, Cy is selected from:

In some embodiments of formula III, Cy is an optionally substitutedgroup selected from:

In some embodiments of formula III, Cy is an optionally substituted 5-6membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. In some embodiments, Cy is a6-membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. In some such embodiments, Cy is anoptionally substituted group selected from pyridinyl. In someembodiments, Cy is an optionally substituted group selected from:

In some embodiments of formula III, Cy is an optionally substitutedgroup selected from:

In some embodiments of formula III, Cy is an optionally substituted 3-10membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments of formula III, Cy is an optionally substituted4-membered saturated heterocyclic group having 1 heteroatomindependently selected from nitrogen, oxygen and sulfur. In some suchembodiments, Cy is optionally substituted oxetanyl. In some suchembodiments, Cy is optionally substituted oxetanyl or azetidinyl.

In some embodiments of formula III, Cy is an optionally substituted5-membered saturated heterocyclic group having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur. In some suchembodiments, Cy is an optionally substituted group selected fromtetrahydrofuranyl and pyrrolidinyl.

In some embodiments of formula III, Cy is an optionally substituted6-membered saturated heterocyclic group having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur. In some suchembodiments, Cy is an optionally substituted group selected fromtetrahydropyranyl and piperidinyl. In some such embodiments, Cy is anoptionally substituted group selected from tetrahydropyranyl,piperidinyl, and piperazinyl.

In some embodiments of formula III, Cy is an optionally substituted7-membered saturated heterocyclic group having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur. It will beappreciated that a 7-membered saturated heterocyclic ring can be abridged bicyclic ring. In some such embodiments, Cy is an optionallysubstituted group selected from:

In some embodiments of formula III, Cy is an optionally substituted8-membered saturated heterocyclic group having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur. It will beappreciated that an 8-membered saturated heterocyclic ring can be abridged bicyclic ring. In some such embodiments, Cy is an optionallysubstituted group selected from:

In some embodiments of formula III, R¹ is fluoro, R² is chloro, andR^(x) is methyl, thus forming a compound of formula III-a:

or a pharmaceutically acceptable salt thereof, wherein Z is as definedabove and described in classes and subclasses herein.

In some embodiments, the present disclosure provides a compound, or apharmaceutically acceptable salt thereof selected from the compoundslisted in Table 2:

TABLE 2 Cmpd No Compound Structure A-1

A-2

A-3

A-4

A-5

A-6

A-7

A-8

A-9

A-10

A-11

A-12

A-13

A-14

A-15

A-16

A-17

A-18

A-19

A-20

A-21

A-22

A-23

A-24

A-25

A-26

A-27

A-28

A-29

A-30

A-31

A-32

Acetyl Transferases

Histone acetylation and deacetylation are processes by which lysineresidues within the N-terminal tail protruding from histone cores of thenucleosome are acetylated and deacetylated. Without wishing to be boundby any particular theory, it is believed that histone acetylation is apart of gene regulation. Histone Acetyltransferases, also known as HATs,are a family of enzymes that acetylate the histone tails of thenucleosome among other nuclear and cytoplasmic non-histone targets. SomeHATs acetylate a lysine residue, and such Lysine Acetyltransferases arealso referred to as KATs.

KATs can be divided into families based on their structure and sequencesimilarity. KAT families include, for example, the Gcn5-relatedN-acetyltransferase (GNAT) family, which includes GCN5 and PCAF, theCREBBP/EP300 family and the MYST (MOZ, Ybf2/Sas3, Sas2, Tip60) family.The MYST family of HATs is named after its four founding members MOZ,Ybf2 (Sas3), Sas2, and Tip60. Other members include Esa1, MOF, MORF, andHBO1. Members of the MYST family are characterized by the presence ofthe MYST catalytic domain, and have been reported to acetylate lysineresidues on histones, e.g., on histone 2A (H2A), histone 3 (H3), andhistone 4 (H4). Lysine acetyltransferases are also referred to as KATs,and members of the MYST family of histone acetyltransferases include,for example, KAT-5 (also sometimes referred to as Tip60), KAT-6A (alsosometimes referred to as MOZ, MYST3, RUNXBP2, or ZNF220), KAT-6B (alsosometimes referred to as MORF, MYST4, or MOZ2), KAT-7 (also sometimesreferred to as (HBO1, HBOa, or MYST2), and KAT-8 (also sometimesreferred to as MOF, YBF2, SAS3, or MYST1).

Different KATs may contain various other domains in addition to the HATdomain which facilitate interactions with other proteins, includingreader domains for acetylation and other modifications. See, e.g.,Farria et al. Oncogene (2015) 34, 4901-4913, incorporated herein byreference. Some KATs, for example those in the GNAT and CREBBP/EP300families, contain bromodomains. Bromodomains help KATs recognize andbind to acetylated lysine residues on histone substrates. Together thesedomains allow for specificity and diversity in KAT substrates. All KATsexamined to date have important functions in cellular differentiationand embryo development. Several KATs have also been associated withoncogenesis. For example, CREBBP/EP300, have been implicated in cancerdevelopment and progression. See, e.g., Farria et al. Oncogene (2015)34, 4901-4913; Lee et al. Nat. Rev. Mol. Cell Biol. 8 (4): 284-95; andAvvakumov et al. Oncogene (2007) 26, 5395-5407, the entire contents ofeach of which are incorporated herein by reference.

Inhibitors of KATs and histone deacetylase inhibitors (HDACs) havepotential as anti-cancer therapies. As noted, KATs within the MYSTfamily are grouped together on the basis of their close sequencesimilarities and their possession of a particular acetyl transferasehomology region. The name is derived from the first four membersidentified: MOZ (KAT-6A), Ybf2/Sas3, Sas2, Tip60 (KAT-5). AdditionalKATs have also been identified, including MOF (KAT-8) and HBO-1 (KAT-7).The MYST catalytic domain that defines the family has a C2HC zinc fingerand an acetyl-CoA binding site. These enzymes are involved intranscription regulation, DNA replication, recombination, and repair.They are directly implicated in the development of a variety ofdiseases, including cancer.

One MYST family HAT of particular interest, KAT-7, also known as LysineAcetyltransferase 7, HBO1, HBOA, MYST2, and ZC2HC7, belongs to the MYSTfamily of histone acetyl transferases and plays an essential role in DNAreplication. The KAT-7 coding region has been identified as a commonretroviral integration site, and KAT-7 has been linked to numerousdisease binding partners, including AR, the von Hippel-Lindau tumoursuppressor, and ING4 and -5. Specific cancers that have been identifiedas being linked to KAT-7 inhibition include, for example, breast cancer,prostate cancer, and leukemia.

The protein sequences of exemplary KAT-7 proteins have been reported.Exemplary human KAT-7 protein sequences include, for example, andwithout limitation, the sequences provided below. Additional KAT-7sequences, including KAT-7 sequences from other species and additionalhuman KAT-7 sequences will be apparent to those of ordinary skill in theart, and include, for example, and without limitation, those KAT-7sequences listed in the NCBI and ENSEMBL gene databases.

NP_008998.1 histone acetyltransferase KAT-7 isoform 1 [Homo sapiens](SEQ ID NO: 1) MPRRKRNAGSSSDGTEDSDFSTDLEHTDSSESDGTSRRSARVTRSSARLSQSSQDSSPVRNLQSFGTEEPAYSTRRVTRSQQQPTPVTPKKYPLRQTRSSGSETEQVVDFSDRETKNTADHDESPPRTPTGNAPSSESDIDISSPNVSHDESIAKDMSLKDSGSDLSHRPKRRRFHESYNFNMKCPTPGCNSLGHLTGKHERHFSISGCPLYHNLSADECKVRAQSRDKQIEERMLSHRQDDNNRHATRHQAPTERQLRYKEKVAELRKKRNSGLSKEQKEKYMEHRQTYGNTREPLLENLTSEYDLDLFRRAQARASEDLEKLRLQGQITEGSNMIKTIAFGRYELDTWYHSPYPEEYARLGRLYMCEFCLKYMKSQTILRRHMAKCVWKHPPGDEIYRKGSISVFEVDGKKNKIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVMTEADNTGCHLIGYFSKEKNSFLNYNVSCILTMPQYMRQGYGKMLIDFSYLLSKVEEKVGSPERPLSDLGLISYRSYWKEVLLRYLHNFQGKEISIKEISQETAVNPVDIVSTLQALQMLKYWKGKHLVLKRQDLIDEWIAKEAKRSNSNKTMDPSCLKWTPPKGTNP_001186084.1 histone acetyltransferase KAT-7  isoform 2 [Homo sapiens](SEQ ID NO: 2) MPRRKRNAGSSSDGTEDSDFSTDLEHTDSSESDGTSRRSARVTRSSARLSQSSQDSSPVRNLQSFGTEEPAYSTRRVTRSQQQPTPVTPKKYPLRQTRSSGSETEQVVDFSDRETKNTADHDESPPRTPTGNAPSSESDIDISSPNVSHDESIAKDMSLKDSGSDLSHRPKRRRFHESYNFNMKCPTPGCNSLGHLTGKHERHFSISGCPLYHNLSADECKAPTERQLRYKEKVAELRKKRNSGLSKEQKEKYMEHRQTYGNTREPLLENLTSEYDLDLFRRAQARASEDLEKLRLQGQITEGSNMIKTIAFGRYELDTWYHSPYPEEYARLGRLYMCEFCLKYMKSQTILRRHMAKCVWKHPPGDEIYRKGSISVFEVDGKKNKIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVMTEADNTGCHLIGYFSKEKNSFLNYNVSCILTMPQYMRQGYGKMLIDFSYLLSKVEEKVGSPERPLSDLGLISYR SYWKEVLLRY LHNFQGKEIS IKEISQETAV NPVDIVSTLQALQMLKYWKGKHLVLKRQDL IDEWIAKEAK RSNSNKTMDP SCLKWTPPKGTNP_001186085.1 histone acetyltransferase KAT-7 isoform 3 [Homo sapiens](SEQ ID NO: 3) MPRRKRNAGSSSDGTEDSDFSTDLEHTDSSESDGTSRRSARVTRSSARLSQSSQGHLTGKHERHFSISGCPLYHNLSADECKVRAQSRDKQIEERMLSHRQDDNNRHATRHQAPTERQLRYKEKVAELRKKRNSGLSKEQKEKYMEHRQTYGNTREPLLENLTSEYDLDLFRRAQARASEDLEKLRLQGQITEGSNMIKTIAFGRYELDTWYHSPYPEEYARLGRLYMCEFCLKYMKSQTILRRHMAKCVWKHPPGDEIYRKGSISVFEVDGKKNKIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVMTEADNTGCHLIGYFSKEKNSFLNYNVSCILTMPQYMRQGYGKMLIDFSYLLSKVEEKVGSPERPLSDLGLISYRSYWKEVLLRYLHNFQGKEISIKEISQETAVNPVDIVSTLQALQMLKYWKGKHLVLKRQDLIDEWIAKEAKRSNSNKTMDPSCLKWTPPK GTNP_001186086.1 histone acetyltransferase KAT-7 isoform 4 [Homo sapiens](SEQ ID NO: 4) MPRRKRNAGSSSDGTEDSDFSTDLEHTDSSESDGTSRRSARVTRSSARLSQSSQDSSPVRNLQSFGTEEPAYSTRRVTRSQQQPTPVTPKKYPLRQTRSSGSETEQVVDFSDRGHLTGKHERHFSISGCPLYHNLSADECKAPTERQLRYKEKVAELRKKRNSGLSKEQKEKYMEHRQTYGNTREPLLENLTSEYDLDLFRRAQARASEDLEKLRLQGQITEGSNMIKTIAFGRYELDTWYHSPYPEEYARLGRLYMCEFCLKYMKSQTILRRHMAKCVWKHPPGDEIYRKGSISVFEVDGKKNKIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVMTEADNTGCHLIGYFSKEKNSFLNYNVSCILTMPQYMRQGYGKMLIDFSYLLSKVEEKVGSPERPLSDLGLISYRSYWKEVLLRYLHNFQGKEISIKEISQETAVNPVDIVSTLQALQMLKYWKGKHLVLKRQDLIDEWIAKEAKRSNSNKTMDPSCLKWTPPKGT NP_001186087.1 histone acetyltransferase KAT-7 isoform 5 [Homo sapiens](SEQ ID NO: 5) MPRRKRNAGSSSDGTEDSDFSTDLEHTDSSESDGTSRRSARVTRSSARLSQSSQGHLTGKHERHFSISGCPLYHNLSADECKAPTERQLRYKEKVAELRKKRNSGLSKEQKEKYMEHRQTYGNTREPLLENLTSEYDLDLFRRAQARASEDLEKLRLQGQITEGSNMIKTIAFGRYELDTWYHSPYPEEYARLGRLYMCEFCLKYMKSQTILRRHMAKCVWKHPPGDEIYRKGSISVFEVDGKKNKIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVMTEADNTGCHLIGYFSKEKNSFLNYNVSCILTMPQYMRQGYGKMLIDFSYLLSKVEEKVGSPERPLSDLGLISYRSYWKEVLLRYLHNFQGKEISIKEISQETAVNPVDIVSTLQALQMLKYWKGKHLVLKRQDLIDEWIAKEAKRS NSNKTMDPSCLKWTPPKGT NP_001333635.1 histone acetyltransferase KAT-7 isoform 6 [Homo sapiens](SEQ ID NO: 6) MPRRKRNAGSSSDGTEDSDFSTDLEHTDSSESDGTSRRSARVTRSSARLSQSSQDSSPVRNLQSFGTEEPAYSTRRVTRSQQQPTPVTPKKYPLRQTRSSGSETEQVVDFSDRGHLTGKHERHFSISGCPLYHNLSADECKVRAQSRDKQIEERMLSHRQDDNNRHATRHQAPTERQLRYKEKVAELRKKRNSGLSKEQKEKYMEHRQTYGNTREPLLENLTSEYDLDLFRRAQARASEDLEKLRLQGQITEGSNMIKTIAFGRYELDTWYHSPYPEEYARLGRLYMCEFCLKYMKSQTILRRHMAKCVWKHPPGDEIYRKGSISVFEVDGKKNKIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVMTEADNTGCHLIGYFSKEKNSFLNYNVSCILTMPQYMRQGYGKMLIDFSYLLSKVEEKVGSPERPLSDLGLISYRSYWKEVLLRYLHNFQGKEISIKEISQETAVNPVDIVSTLQALQMLKYWKGKHLVLKRQDLIDEWIAKEAKRSNSNKT MDPSCLKWTPPKGT

In some embodiments, the present disclosure provides inhibitors of MYSTfamily KATs, e.g., of KAT-5, KAT-6A, KAT-7, and/or KAT-8, for use ashistone acetyltransferase inhibitors, e.g., in vitro or in vivo. Incertain embodiments, the present disclosure provides inhibitors of MYSTfamily KATs, e.g., KAT-5, KAT-6A, KAT-7, and/or KAT-8, for use intreating diseases or disorders that are characterized by an abnormalMYST family KAT activity, e.g., certain cancers.

Some aspects of this disclosure provide methods for modulating proteinacetylation, e.g., histone acetylation, e.g., in a cell or tissue, bycontacting a histone acetylase, e.g., KAT-5, KAT-6A, KAT-7, and/orKAT-8, or a cell or tissue expressing such a histone acetylase, withcompounds of the present disclosure in an amount sufficient to modulatethe activity of the histone acetylase, e.g., of KAT-5, KAT-6A, KAT-7,and/or KAT-8, e.g., as measured by a reduction in the acetylation of atarget protein of the histone acetyltransferase, e.g., a histoneacetylated by KAT-5, KAT-6A, KAT-7, and/or KAT-8 activity. In someembodiments, the contacting is in vitro. In some embodiments, thecontacting is in vivo, e.g., by administering the compounds of thepresent disclosure, or a pharmaceutically acceptable salt thereof, to asubject, e.g., a human subject. In some embodiments, the subject is asubject having or diagnosed with a cancer or a precancerous condition.

Some aspects of this disclosure provide methods for selectivelyinhibiting at least one KAT. For example, in some embodiments, it isbeneficial to be able to selectively inhibit a specific MYST family KATor a combination of two or more MYST family KATs, while not inhibitingone or more different KATs, or while inhibiting one or more differentKATs to a lesser extent. As used herein, the term “selectivelyinhibiting” refers to inhibiting of a particular MYST family KAT, or agroup of MYST family KATs, while inhibiting a different KAT or a groupof KATs to a different extent.

For example, in some embodiments, selectively inhibiting a MYST familyKAT, refers to inhibiting the activity of the MYST family KAT at apotency that is at least 2-fold, at least 5-fold, at least 10-fold, atleast 15-fold, at least 20-fold, at least 25-fold, at least 50-fold, atleast 75-fold, at least 100-fold, at least 200-fold, at least 250-fold,at least 500-fold, at least 750-fold, at least 1000-fold, at least2000-fold, at least 2500-fold, at least 5000-fold, at least 7500-fold,or at least 10000-fold the potency at which a different KAT, e.g., adifferent MYST family KAT is inhibited.

The potency of inhibition of a given KAT inhibitor can be determined,e.g., measured, by methods well known to those of skill in the art. Someexemplary methods are provided herein, and other suitable methods willbe apparent to the skilled artisan based on the present disclosure andthe general knowledge in the art. One exemplary suitable measure ofinhibition potency is the IC₅₀ value of a given KAT inhibitory compoundwith regard to a specific KAT enzyme, e.g., as exemplified for somecompounds and some MYST family KATs elsewhere herein. Since the IC₅₀value is a measure of the concentration of a given inhibitor to achievea certain level of inhibition, it will be understood that a lower IC₅₀value indicates a more potent inhibition. To provide a non-limitingexample, a KAT-7 inhibitor would be said to inhibit KAT-7 at a potencythat is 10-fold the potency at which it inhibits KAT-5, if the IC₅₀ ofthat inhibitor with regard to KAT-7 is 10-fold lower than the IC₅₀ ofthe inhibitor with regard to KAT-5.

Other measures of inhibition potency are also suitable, e.g., the levelof inhibition of activity of a specific KAT at a given inhibitorconcentration, e.g., as compared to the activity of the KAT in theabsence of the inhibitor. To provide a non-limiting example, a KAT-7inhibitor would be said to inhibit KAT-7 at a potency that is 10-foldthe potency at which it inhibits KAT-5, if exposure of KAT-7 to theinhibitor results in a 10-fold greater inhibition of KAT-7 activity thanthe inhibition of KAT-5 activity that is achieved by exposure of KAT-5to the inhibitor at the same concentration in the same assay.

Some exemplary, non-limiting suitable measures to compare inhibitionpotency of a given inhibitor amongst different KATs are provided herein,as are suitable assays (e.g., biochemical or cellular assays) fordetermining inhibition potency of a given KAT inhibitor, and additionalsuitable measures and assays will be apparent to the person of ordinaryskill in the art in view of the present disclosure and the knowledge inthe art. The disclosure is not limited in this respect.

In some embodiments, the present disclosure provides compounds (e.g.,compounds of formula I, formula I-a, formula II, formula II-a, formulaII-b, formula II-b, formula III, and/or formula III-a) and methods forselectively inhibiting a specific MYST family KAT, e.g., KAT-5, KAT-6A,KAT-7, or KAT-8, as compared to a different KAT, e.g., a different MYSTfamily KAT. In some embodiments, the present disclosure providescompounds (e.g., compounds of formula I′, formula I, formula I-a,formula II, formula II-a, formula II-b, formula II-c, formula III,and/or formula III-a) and methods for selectively inhibiting a specificMYST family KAT, e.g., KAT-5, KAT-6A, KAT-7, or KAT-8, as compared to adifferent KAT, e.g., a different MYST family KAT. For example, in someembodiments, the present disclosure provides compounds and methods forselectively inhibiting KAT-7 as compared to KAT-5. In some embodiments,the present disclosure provides compounds and methods for selectivelyinhibiting a group of MYST family KATs, e.g., KAT-7 and KAT-6A, ascompared to a different KAT, e.g., a MYST family KAT, e.g., as comparedto KAT-5. In some embodiments, the present disclosure provides compoundsand methods for selectively inhibiting KAT-7 and KAT-8 as compared toKAT-5. In some embodiments, the present disclosure provides compoundsand methods for selectively inhibiting KAT-7, KAT-6A, and KAT-8 ascompared to KAT-5. In some embodiments, the present disclosure providescompounds and methods for selectively inhibiting KAT-7 as compared toKAT-5 and KAT-6A. In some embodiments, the present disclosure providescompounds and methods for selectively inhibiting KAT-7 as compared toKAT-5 and KAT-8. In some embodiments, the present disclosure providescompounds and methods for selectively inhibiting KAT-7 as compared toKAT-5, KAT-6A, and KAT-8.

In some embodiments, the present disclosure provides compounds andmethods for selectively inhibiting KAT-7 and KAT-6A as compared to KAT-5and KAT-8. In some embodiments, the present disclosure providescompounds and methods for selectively inhibiting KAT-7 and KAT-8 ascompared to KAT-5 and KAT-6A.

In some embodiments, the present disclosure provides compounds thatselectively inhibit a single MYST-family KAT, e.g., KAT-7. In someembodiments, the present disclosure provides compounds that selectivelyinhibit two MYST-family KATs (dual inhibitors), e.g., KAT-7 and KAT-6A,or KAT-7 and KAT-8. In some embodiments, the present disclosure providescompounds that selectively inhibit three MYST family KATs (tripleinhibitors), e.g., KAT-7, KAT-6A, and KAT-8. It will be appreciated thatthe assays and experiments described below facilitate thecharacterization and/or identification of compounds that inhibit one ormore MYST family KATs. Persons skilled in the art performing and/orusing the assays and experiments described herein can readily identifyother inhibitors of MYST family KATs, and therefore can determine whichcompounds selectively inhibit certain MYST family KATs compared to otherMYST family KATs.

Cancers and Tumors

The present disclosure provides, inter alia, compounds and compositionsuseful in the treatment of cancer, e.g., for the treatment of a tumor ina subject.

In some embodiments, the present disclosure provides a method oftreating a disease or disorder associated with a MYST family KAT, e.g.,with KAT-5, KAT-6A, KAT-7, and/or KAT-8. In certain embodiments, thedisease or disorder is a KAT-7-mediated disorder. In certainembodiments, the disease or disorder is a KAT-6A-mediated disorder. Incertain embodiments, the disease or disorder is a KAT-8-mediateddisorder. In certain embodiments, the disease or disorder is aKAT-5-mediated disorder.

Cancers that can be treated with the methods and compositions providedherein, e.g., include, for example, adrenocortical carcinoma,astrocytoma, basal cell carcinoma, carcinoid, cardiac,cholangiocarcinoma, chordoma, chronic myeloproliferative neoplasms,craniopharyngioma, ductal carcinoma in situ, ependymoma, intraocularmelanoma, gastrointestinal carcinoid tumor, gastrointestinal stromaltumor (GIST), gestational trophoblastic disease, glioma, histiocytosis,leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenousleukemia (CVIL), hairy cell leukemia, myelogenous leukemia, and myeloidleukemia), lymphoma (e.g., Burkitt lymphoma (non-Hodgkin lymphoma),cutaneous T-cell lymphoma, Hodgkin lymphoma, mycosis fungoides, Sezarysyndrome, AIDS-related lymphoma, follicular lymphoma, diffuse largeB-cell lymphoma), melanoma, merkel cell carcinoma, mesothelioma, myeloma(e.g., multiple myeloma), myelodysplastic syndrome, papillomatosis,paraganglioma, pheochromacytoma, pleuropulmonary blastoma,retinoblastoma, sarcoma (e.g., Ewing sarcoma, Kaposi sarcoma,osteosarcoma, rhabdomyosarcoma, uterine sarcoma, vascular sarcoma),Wilms' tumor, and/or cancer of the adrenal cortex, anus, appendix, bileduct, bladder, bone, brain, breast, bronchus, central nervous system,cervix, colon, endometrium, esophagus, eye, fallopian tube, gallbladder, gastrointestinal tract, germ cell, head and neck, heart,intestine, kidney (e.g., Wilms' tumor), larynx, liver, lung (e.g.,non-small cell lung cancer, small cell lung cancer), mouth, nasalcavity, oral cavity, ovary, pancreas, rectum, skin, stomach, testes,throat, thyroid, penis, pharynx, peritoneum, pituitary, prostate,rectum, salivary gland, ureter, urethra, uterus, vagina, or vulva.

In some embodiments, the present disclosure provides methods andcompositions for treating a tumor in a subject. In some embodiments, thetumor is a solid tumor. In some embodiments, the tumor is a liquid ordisperse tumor. In some embodiments, the tumor is associated with ahematologic malignancy, including but not limited to, acutelymphoblastic leukemia, acute myeloid leukemia, chronic lymphocyticleukemia, chronic myelogenous leukemia, hairy cell leukemia,AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma,follicular lymphoma, diffuse large B-cell lymphoma, Langerhans cellhistiocytosis, multiple myeloma, or myeloproliferative neoplasms.

In some embodiments, a tumor comprises a solid tumor. In someembodiments, solid tumors include but are not limited to tumors of thebladder, breast, central nervous system, cervix, colon, esophagus,endometrium, head and neck, kidney, liver, lung, ovary, pancreas, skin,stomach, uterus, or upper respiratory tract. In some embodiments, atumor that may be treated by the compositions and methods of the presentdisclosure is a breast tumor. In some embodiments, a tumor that may betreated by the compositions and methods of the present disclosure is nota lung tumor.

In some embodiments, a tumor or cancer suitable for treatment with themethods and compositions provided herein includes, for example, acutelymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenalcortex cancer, adrenocortical carcinoma, AIDS-related cancer (e.g.,Kaposi sarcoma, AIDS-related lymphoma, primary CNS lymphoma), analcancer, appendix cancer, astrocytoma, atypical rhabdoid tumor, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer, braintumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoidtumor, carcinoma, cardiac (heart) tumor, central nervous system tumor,cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), chronicmyeloproliferative neoplasm, colorectal cancer, craniopharyngioma,cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonaltumor, endometrial cancer, endometrial sarcoma, ependymoma, esophageal,esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, eye cancer, fallopian tube cancer,gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoidtumor, gastrointestinal stromal tumor (GIST), germ cell tumor,gestational trophoblastic disease, glioma, hairy cell leukemia, head andneck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma,hypopharyngeal cancer, intraocular melanoma, islet cell tumor, Kaposisarcoma, kidney tumor, Langerhans cell histiocytosis, laryngeal cancer,leukemia, lip and oral cavity cancer, liver cancer, lung cancer,lymphoma, male breast cancer, malignant fibrous histiocytoma, melanoma,Merkel cell carcinoma, mesothelioma, mouth cancer, multiple endocrineneoplasia syndrome, multiple myeloma, plasma cell neoplasm, mycosisfungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferativeneoplasm, nasal cavity cancer, nasopharyngeal cancer, neuroblastoma,non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oralcavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer,pancreatic cancer, pancreatic neuroendocrine tumor (islet cell tumor),paraganglioma, paranasal sinus cancer, parathyroid cancer, penilecancer, pharyngeal cancer, pheochromocytoma, pituitary tumor,pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma,primary peritoneal cancer, prostate cancer, rectal cancer, renal cell(kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary glandcancer, sarcoma, Sezary syndrome, skin cancer, small intestine cancer,soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer,stomach (gastric) cancer, T-cell lymphoma, testicular cancer, throatcancer, thymic carcinoma, thymoma, thyroid cancer, urethral cancer,uterine sarcoma, vaginal cancer, vascular tumor, vulvar cancer,Waldenström macroglobulinemia, or Wilms' tumor.

Pharmaceutical Compositions

In some embodiments, the present disclosure provides a pharmaceuticalcomposition comprising an inhibitor of a MYST family KAT, e.g., ofKAT-5, KAT-6, KAT-7, and/or KAT-8, as described herein. In someembodiments, the compounds of the present disclosure (e.g., compounds offormula I, formula I-a, formula II, formula II-a, formula II-b, formulaII-c, formula III, and/or formula III-a), can be administered to asubject, e.g., to a human patient, alone, e.g., in the form of apharmaceutically acceptable salt, a solvated or hydrated form ofcompounds of the present disclosure, and any polymorph or crystal formthereof. In some embodiments, the compounds of the present disclosure(e.g., compounds of formula I′, formula I, formula I-a, formula II,formula II-a, formula II-b, formula II-c, formula III, and/or formulaIII-a), can be administered to a subject, e.g., to a human patient,alone, e.g., in the form of a pharmaceutically acceptable salt, asolvated or hydrated form of compounds of the present disclosure, andany polymorph or crystal form thereof. In some embodiments, thecompounds of the present disclosure, can be administered in the form ofa pharmaceutical composition, e.g., where the compounds of the presentdisclosure are admixed with a suitable carrier or excipient. Apharmaceutical composition typically comprises or can be administered ata dose sufficient to treat or ameliorate a disease or condition in therecipient subject, e.g., to treat or ameliorate a cancer as describedherein. Accordingly, a pharmaceutical composition is formulated in amanner suitable for administration to a subject, e.g., in that it isfree from pathogens and formulated according to the applicableregulatory standards for administration to a subject, e.g., foradministration to a human subject. As an example, a formulation forinjection is typically sterile and essentially pyrogen-free.

Compounds of the present disclosure can also be administered to asubject as a mixture with other agents, e.g., with one or moreadditional therapeutic agent(s), e.g., in a suitably formulatedpharmaceutical composition. For example, some aspects of the presentdisclosure relate to pharmaceutical compositions comprising atherapeutically effective dose of compounds of the present disclosure,or a pharmaceutically acceptable salt, hydrate, enantiomer orstereoisomer thereof; and a pharmaceutically acceptable diluent orcarrier.

Techniques for formulation and administration of compounds of thepresent disclosure may be found in references well known to one ofordinary skill in the art, such as Remington's “The Science and Practiceof Pharmacy,” 21st ed., Lippincott Williams & Wilkins 2005, the entirecontents of which are incorporated herein by reference.

Pharmaceutical compositions as provided herein are typically formulatedfor a suitable route of administration. Suitable routes ofadministration may, for example, include enteral administration, e.g.,oral, rectal, or intestinal administration; parenteral administration,e.g., intravenous, intramuscular, intraperitoneal, subcutaneous, orintramedullary injection, as well as intrathecal, directintraventricular, or intraocular injections; topical delivery, includingeyedrop and transdermal; and intranasal and other transmucosal delivery,or any suitable route provided herein or otherwise apparent to those ofordinary skill in the art.

The pharmaceutical compositions provided herein may be manufactured,e.g., by mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping, or lyophilizing processes, or byany other suitable processes known to those of ordinary skill in theart.

Pharmaceutical compositions for use in accordance with the presentdisclosure may be formulated using one or more physiologicallyacceptable carriers comprising excipients and auxiliaries whichfacilitate processing of compounds of the present disclosure intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For injection, the agents of the disclosure may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks' solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants are used in the formulationappropriate to the barrier to be permeated. Such penetrants aregenerally known in the art.

For oral administration, compounds of the present disclosure can beformulated readily by combining the compound with pharmaceuticallyacceptable carriers known in the art. Such carriers enable compounds ofthe present disclosure to be formulated as tablets, pills, dragees,capsules, liquids, gels, syrups, slurries, suspensions and the like, fororal ingestion by a patient to be treated. Pharmaceutical preparationsfor oral use can be obtained by combining the compounds of the presentdisclosure with a solid excipient, optionally grinding a resultingmixture, and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients include fillers such as sugars, including lactose, sucrose,mannitol, or sorbitol; cellulose preparations such as, for example,maize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredient(s), e.g., compounds of thepresent disclosure, in admixture with filler such as lactose, binderssuch as starches, and/or lubricants such as talc or magnesium stearateand, optionally, stabilizers. In soft capsules, the compounds of thepresent disclosure may be dissolved or suspended in suitable liquids,such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers may be added.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, compounds of the present disclosurefor use according to the present disclosure is conveniently delivered inthe form of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof e.g., gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compounds of the present disclosure and asuitable powder base such as lactose or starch.

Suitable compound(s) of the present disclosure can be formulated forparenteral administration by injection, e.g., bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form, e.g., in ampoules, or in multi-dose containers, and, insome embodiments, may contain an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of compound(s) of the present disclosure inwater-soluble form. Additionally, suspensions of compound(s) of thepresent disclosure may be prepared as appropriate injection suspensions,e.g., aqueous or oily injection suspensions. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility ofcompound(s) of the present disclosure to allow for the preparation ofhighly concentrated solutions.

Alternatively, the active ingredient(s), e.g., compound(s) of thepresent disclosure, may be in powder form for reconstitution before usewith a suitable vehicle, e.g., sterile pyrogen-free water.

Compound(s) of the present disclosure may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases, such as cocoa butter or otherglycerides.

In addition to the formulations described previously, compounds of thepresent disclosure may also be formulated as a depot preparation. Suchlong acting formulations may be administered by implantation (forexample, subcutaneously or intramuscularly or by intramuscularinjection). Thus, for example, compounds of the present disclosure maybe formulated with suitable polymeric or hydrophobic materials (forexample as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives (for example, as a sparingly solublesalt).

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompound(s) of the present disclosure may be employed. Liposomes andemulsions are examples of delivery vehicles or carriers for hydrophobicdrugs. Certain organic solvents such as dimethylsulfoxide also may beemployed. Additionally, compounds of the present disclosure may bedelivered using a sustained-release system, such as semi-permeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials have been established and are wellknown by those skilled in the art. Sustained-release capsules may,depending on their chemical nature, release the compound(s) of thepresent disclosure for a few hours, a few days, a few weeks, or a fewmonths, e.g., up to over 100 days.

The pharmaceutical compositions may also comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymers,such as polyethylene glycols.

Additional suitable pharmaceutical compositions and processes andstrategies for formulating a suitable compound of the present disclosurewill be apparent to the skilled artisan based on the present disclosure.The disclosure is not limited in this respect.

Methods of Treatment

Some aspects of this disclosure provide methods for modulating proteinacetylation, e.g., histone acetylation, in a subject in need thereof byadministering compounds of the present disclosure to the subject in anamount sufficient to modulate acetylation of a target protein, e.g., ahistone acetylated by a MYST family KAT, e.g., by KAT-5, KAT-6, KAT-7,and/or KAT-8, activity. In some embodiments, the subject is a subjecthaving or diagnosed with a cancer or a precancerous condition.

Provided herein are methods of treating, preventing or alleviating asymptom of conditions and diseases, such as cancers and precancerousconditions, the course of which can be influenced by modulating theacetylation status of histones or other proteins that are acetylated bya MYST family KAT, e.g., by KAT-5, KAT-6, KAT-7, and/or KAT-8, whereinsaid acetylation status is mediated at least in part by the activity ofCREBBP. Modulation of the acetylation status of histones can in turninfluence the level of expression of target genes activated byacetylation, and/or target genes suppressed by acetylation.

For example, some aspects of the disclosure provide methods for treatingor alleviating a symptom of cancer or precancerous condition. In someembodiments, the method comprises the step of administering to a subjecthaving a cancer or a precancerous condition compounds of the presentdisclosure, e.g., in the form of a pharmaceutical composition, at atherapeutically effective amount.

In some embodiments, compounds of the present disclosure inhibit histoneacetyltransferase activity of a MYST family KAT, e.g., of KAT-5, KAT-6,KAT-7, and/or KAT-8. In some embodiments, compounds of the presentdisclosure selectively inhibit histone acetyltransferase activity of aMYST family KAT, e.g., of KAT-5, KAT-6, KAT-7, and/or KAT-8.

In some embodiments, the subject is diagnosed with a disease or disorderknown to be associated with a dysregulation of histone acetylation,e.g., with a dysfunction of a MYST family KAT, e.g., of KAT-5, KAT-6,KAT-7, and/or KAT-8. In some embodiments, the subject is diagnosed witha disease or disorder mediated by a MYST family KAT, e.g., by KAT-5,KAT-6, KAT-7, and/or KAT-8. In some embodiments, the subject has beendiagnosed with a cancer.

Dysregulated histone acetylation has been reported to be involved inaberrant expression of certain genes in cancers and other diseases.Compounds described herein can be used to treat such histoneacetylation-associated diseases, e.g., to inhibit histone acetylationmediated by a MYST family KAT, e.g., KAT-5-, KAT-6-, KAT-7-, and/orKAT-8-mediated histone acetylation in affected cells, tissues, orsubjects.

Modulators of histone acetylation can be used for modulating cellproliferation, e.g., of cells harboring a mutation resulting in aberranthistone acetylation, or for inducing cell death in cells depending onhistone acetylation by a MYST family KAT, e.g., by KAT-5, KAT-6, KAT-7,and/or KAT-8, histone acetylation for survival or proliferation.Accordingly, diseases that may be treated with compound(s) of thepresent disclosure include hyperproliferative diseases, such as benigncell growth and malignant cell growth (cancer).

Exemplary cancers that may be treated with a compound provided hereininclude, without limitation, lymphomas, including non-Hodgkin lymphoma,follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL);melanoma; leukemia, including CML; acute lymphoblastic leukemia; acutemyeloid leukemia; adrenocortical carcinoma; AIDS-related cancers;AIDS-related lymphoma; anal cancer; astrocytoma, childhood cerebellar;basal cell carcinoma, see skin cancer (non-melanoma); bile duct cancer,extrahepatic; bladder cancer; bone cancer, osteosarcoma/malignantfibrous histiocytoma; brain stem glioma; brain tumor; brain tumor,cerebellar astrocytoma; brain tumor, cerebral astrocytoma/malignantglioma; brain tumor, ependymoma; brain tumor, medulloblastoma; braintumor, supratentorial primitive neuroectodermal tumors; brain tumor,visual pathway and hypothalamic glioma; breast cancer; bronchialadenomas/carcinoids; Burkitt's lymphoma; carcinoid tumor; carcinoidtumor, gastrointestinal; carcinoma of unknown primary; central nervoussystem lymphoma, primary; cerebellar astrocytoma; cervical cancer;childhood cancers; chronic lymphocytic leukemia; chronic myelogenousleukemia; chronic myelogenous leukemia, hairy cell; chronicmyeloproliferative disorders; colon cancer; colorectal cancer; cutaneousT-cell lymphoma, see mycosis fungoides and Sezary syndrome; endometrialcancer; esophageal cancer; Ewing's family of tumors; extrahepatic bileduct cancer; eye cancer, intraocular melanoma; eye cancer,retinoblastoma; gallbladder cancer; gastric (stomach) cancer;gastrointestinal carcinoid tumor; germ cell tumor, extracranial; germcell tumor, extragonadal; germ cell tumor, ovarian; gestationaltrophoblastic tumor; glioma; glioma, childhood brain stem; glioma,childhood cerebral astrocytoma; glioma, childhood visual pathway andhypothalamic; hairy cell leukemia; head and neck cancer; hepatocellular(liver) cancer, adult (primary); hepatocellular (liver) cancer,childhood (primary); Hodgkin's lymphoma; Hodgkin's lymphoma duringpregnancy; hypopharyngeal cancer; hypothalamic and visual pathwayglioma; intraocular melanoma; islet cell carcinoma (endocrine pancreas);Kaposi's sarcoma; kidney (renal cell) cancer; kidney cancer; laryngealcancer; leukemia; lip and oral cavity cancer; liver cancer, adult(primary); liver cancer, childhood (primary); lung cancer, non-smallcell; lung cancer, small cell; lymphoma, primary central nervous system;macroglobulinemia, Waldenstrom's; malignant fibrous histiocytoma ofbone/osteosarcoma; medulloblastoma; melanoma; Merkel cell carcinoma;mesothelioma; mesothelioma, adult malignant; metastatic squamous neckcancer with occult primary; multiple endocrine neoplasia syndrome;multiple myeloma; multiple myeloma/plasma cell neoplasm mycosisfungoides; myelodysplastic syndromes; myelodysplastic/myeloproliferativediseases; myeloid leukemia, adult acute; myeloid leukemia, childhoodacute; myeloproliferative disorders, chronic; nasal cavity and paranasalsinus cancer; nasopharyngeal cancer; neuroblastoma; non-Hodgkin'slymphoma; non-Hodgkin's lymphoma during pregnancy; oral cancer; oralcavity cancer, lip and; oropharyngeal cancer; osteosarcoma/malignantfibrous histiocytoma of bone; ovarian cancer; ovarian epithelial cancer;ovarian low malignant potential tumor; pancreatic cancer; pancreaticcancer, islet cell; paranasal sinus and nasal cavity cancer; parathyroidcancer; penile cancer; pheochromocytoma; pineoblastoma andsupratentorial primitive neuroectodermal tumors; pituitary tumor; plasmacell neoplasm/multiple myeloma; pleuropulmonary blastoma; pregnancy andbreast cancer; prostate cancer; rectal cancer; retinoblastoma;rhabdomyosarcoma; salivary gland cancer; sarcoma, Ewing's family oftumors; sarcoma, soft tissue; sarcoma, uterine; Sezary syndrome; skincancer; skin cancer (non-melanoma); small intestine cancer; soft tissuesarcoma; squamous cell carcinoma, see skin cancer (non-melanoma);squamous neck cancer with occult primary, metastatic; stomach (gastric)cancer; testicular cancer; thymoma; thymoma and thymic carcinoma;thyroid cancer; transitional cell cancer of the renal pelvis and ureter;trophoblastic tumor, gestational; unknown primary site, cancer of;unusual cancers of childhood; urethral cancer; uterine cancer,endometrial; uterine sarcoma; vaginal cancer; visual pathway andhypothalamic glioma; vulvar cancer; Waldenstrom's macroglobulinemia;Wilms' tumor; and women's cancers. Exemplary precancerous conditionsthat can be treated with compound(s) of the present disclosure includemyelodisplastic syndrome (MDS; formerly known as preleukemia).

Any other disease in which histone acetylation mediated by a MYST familyKAT, e.g., by KAT-5, KAT-6, KAT-7, and/or KAT-8, plays a role may betreatable or preventable using compounds and methods described herein.

Administration

In some embodiments, an active agent for use in accordance with thepresent disclosure is formulated, dosed, and/or administered in atherapeutically effective amount using pharmaceutical compositions anddosing regimens that are consistent with good medical practice andappropriate for the relevant agent(s) and subject(s). In principle,therapeutic compositions can be administered by any appropriate methodknown in the art, including, without limitation, oral, mucosal,by-inhalation, topical, buccal, nasal, rectal, or parenteral (e.g.intravenous, infusion, intratumoral, intranodal, subcutaneous,intraperitoneal, intramuscular, intradermal, transdermal, or other kindsof administration involving physical breaching of a tissue of a subjectand administration of the therapeutic composition through the breach inthe tissue).

In some embodiments, a dosing regimen for a particular active agent mayinvolve intermittent or continuous (e.g., by perfusion or other slowrelease system) administration, for example to achieve a particulardesired pharmacokinetic profile or other pattern of exposure in one ormore tissues or fluids of interest in the subject receiving therapy.

In some embodiments, different agents administered in combination may beadministered via different routes of delivery and/or according todifferent schedules. Alternatively or additionally, in some embodiments,one or more doses of a first active agent is administered substantiallysimultaneously with, and in some embodiments via a common route and/oras part of a single composition with, one or more other active agents.

Factors to be considered when optimizing routes and/or dosing schedulefor a given therapeutic regimen may include, for example, the particularindication being treated, the clinical condition of a subject (e.g.,age, overall health, prior therapy received and/or response thereto) thesite of delivery of the agent, the nature of the agent (e.g. smallmolecule, an antibody or other polypeptide-based compound), the modeand/or route of administration of the agent, the presence or absence ofcombination therapy, and other factors known to medical practitioners.For example, in the treatment of cancer, relevant features of theindication being treated may include, for example, one or more of cancertype, stage, and location.

In some embodiments, one or more features of a particular pharmaceuticalcomposition and/or of a utilized dosing regimen may be modified overtime (e.g., increasing or decreasing the amount of active agent in anyindividual dose, increasing or decreasing time intervals between doses),for example in order to optimize a desired therapeutic effect orresponse.

In general, type, amount, and frequency of dosing of active agents inaccordance with the present disclosure are governed by safety andefficacy requirements that apply when one or more relevant agent(s)is/are administered to a mammal, preferably a human. In general, suchfeatures of dosing are selected to provide a particular, and typicallydetectable, therapeutic response as compared to what is observed absenttherapy.

In the context of the present disclosure, an exemplary desirabletherapeutic response may involve, but is not limited to, inhibition ofand/or decreased tumor growth, tumor size, metastasis, one or more ofthe symptoms and side effects that are associated with a tumor, as wellas increased apoptosis of cancer cells, therapeutically relevantdecrease or increase of one or more cell marker or circulating markers.Such criteria can be readily assessed by any of a variety ofimmunological, cytological, and other methods that are disclosed in theliterature.

In some embodiments, an effective dose (and/or a unit dose) of an activeagent, may be at least about 0.01 μg/kg body weight, at least about 0.05μg/kg body weight, at least about 0.1 μg/kg body weight, at least about1 μg/kg body weight, at least about 2.5 μg/kg body weight, at leastabout 5 μg/kg body weight, and not more than about 100 μg/kg bodyweight. It will be understood by one of skill in the art that in someembodiments such guidelines may be adjusted for the molecular weight ofthe active agent. The dosage may also be varied for route ofadministration, the cycle of treatment, or consequently to doseescalation protocol that can be used to determine the maximum tolerateddose and dose limiting toxicity (if any) in connection to theadministration of compounds of the present disclosure and/or anadditional therapeutic agent at increasing doses. Consequently, therelative amounts of the each agent within a pharmaceutical compositionmay also vary, for example, each composition may comprise between 0.001%and 100% (w/w) of the corresponding agent.

In some embodiments, a “therapeutically effective amount” or“therapeutically effective dose” is an amount of a compound of thepresent disclosure, or a combination of two or more compounds of thepresent disclosure, or a combination of compounds of the presentdisclosure with one or more additional therapeutic agent(s), whichinhibits, totally or partially, the progression of the condition oralleviates, at least partially, one or more symptoms of the condition.In some embodiments, a therapeutically effective amount can be an amountwhich is prophylactically effective. In some embodiments, an amountwhich is therapeutically effective may depend upon a patient's sizeand/or gender, the condition to be treated, severity of the conditionand/or the result sought. In some embodiments, a therapeuticallyeffective amount refers to that amount of a compound of the presentdisclosure that results in amelioration of at least one symptom in apatient. In some embodiments, for a given patient, a therapeuticallyeffective amount may be determined by methods known to those of skill inthe art.

In some embodiments, toxicity and/or therapeutic efficacy of compoundsof the present disclosure can be determined by standard pharmaceuticalprocedures in cell cultures or experimental animals, e.g., fordetermining the maximum tolerated dose (MTD) and the ED₅₀ (effectivedose for 50% maximal response). Typically, the dose ratio between toxicand therapeutic effects is the therapeutic index; in some embodiments,this ratio can be expressed as the ratio between MTD and ED₅₀. Dataobtained from such cell culture assays and animal studies can be used informulating a range of dosage for use in humans.

In some embodiments, dosage may be guided by monitoring the effect ofcompounds of the present disclosure on one or more pharmacodynamicmarkers of enzyme inhibition (e.g., histone acetylation or target geneexpression) in diseased or surrogate tissue. For example, cell cultureor animal experiments can be used to determine the relationship betweendoses required for changes in pharmacodynamic markers and doses requiredfor therapeutic efficacy can be determined in cell culture or animalexperiments or early stage clinical trials. In some embodiments, dosageof compounds of the present disclosure lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. In some embodiments, dosage may vary within such a range, forexample depending upon the dosage form employed and/or the route ofadministration utilized. The exact formulation, route of administrationand dosage can be chosen by the individual physician in view of thepatient's condition. In the treatment of crises or severe conditions,administration of a dosage approaching the MTD may be required to obtaina rapid response.

In some embodiments, dosage amount and/or interval may be adjustedindividually, for example to provide plasma levels of an active moietywhich are sufficient to maintain, for example a desired effect, or aminimal effective concentration (MEC) for a period of time required toachieve therapeutic efficacy. In some embodiments, MEC for particularcompounds of the present disclosure can be estimated, for example, fromin vitro data and/or animal experiments. Dosages necessary to achievethe MEC will depend on individual characteristics and route ofadministration. In some embodiments, high pressure liquid chromatography(HPLC) assays or bioassays can be used to determine plasmaconcentrations.

In some embodiments, dosage intervals can be determined using the MECvalue. In certain embodiments, compound(s) of the present disclosureshould be administered using a regimen which maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90% until the desired amelioration of a symptom isachieved. In other embodiments, different MEC plasma levels will bemaintained for differing amounts of time. In cases of localadministration or selective uptake, the effective local concentration ofthe drug may not be related to plasma concentration.

One of skill in the art can select from a variety of administrationregimens and will understand that an effective amount of particularcompounds of the present disclosure may be dependent on the subjectbeing treated, on the subject's weight, the severity of the affliction,the manner of administration and/or the judgment of the prescribingphysician.

Combination Therapy

In some embodiments, compounds of the present disclosure can be used incombination with another therapeutic agent to treat diseases such ascancer. In some embodiments, compounds of the present disclosure, or apharmaceutical composition thereof, can optionally be administered incombination with one or more additional therapeutic agents, such as acancer therapeutic agent, e.g., a chemotherapeutic agent or a biologicalagent. An additional agent can be, for example, a therapeutic agent thatis art-recognized as being useful to treat the disease or conditionbeing treated by compounds of the present disclosure, e.g., ananti-cancer agent, or an agent that ameliorates a symptom associatedwith the disease or condition being treated. The additional agent alsocan be an agent that imparts a beneficial attribute to the therapeuticcomposition (e.g., an agent that affects the viscosity of thecomposition). For example, in some embodiments, compounds of the presentdisclosure are administered to a subject who has received, is receiving,and/or will receive therapy with another therapeutic agent or modality(e.g., with a chemotherapeutic agent, surgery, radiation, or acombination thereof).

Some embodiments of combination therapy modalities provided by thepresent disclosure provide, for example, administration of compounds ofthe present disclosure and additional agent(s) in a singlepharmaceutical formulation. Some embodiments provide administration ofcompounds of the present disclosure and administration of an additionaltherapeutic agent in separate pharmaceutical formulations.

Examples of chemotherapeutic agents that can be used in combination withcompounds of the present disclosure described herein include platinumcompounds (e.g., cisplatin, carboplatin, and oxaliplatin), alkylatingagents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogenmustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin,temozolomide, dacarbazine, and bendamustine), antitumor antibiotics(e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone,bleomycin, mytomycin C, plicamycin, and dactinomycin), taxanes (e.g.,paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil,cytarabine, premetrexed, thioguanine, floxuridine, capecitabine, andmethotrexate), nucleoside analogues (e.g., fludarabine, clofarabine,cladribine, pentostatin, and nelarabine), topoisomerase inhibitors(e.g., topotecan and irinotecan), hypomethylating agents (e.g.,azacitidine and decitabine), proteosome inhibitors (e.g., bortezomib),epipodophyllotoxins (e.g., etoposide and teniposide), DNA synthesisinhibitors (e.g., hydroxyurea), vinca alkaloids (e.g., vicristine,vindesine, vinorelbine, and vinblastine), tyrosine kinase inhibitors(e.g., imatinib, dasatinib, nilotinib, sorafenib, and sunitinib),nitrosoureas (e.g., carmustine, fotemustine, and lomustine),hexamethylmelamine, mitotane, angiogenesis inhibitors (e.g., thalidomideand lenalidomide), steroids (e.g., prednisone, dexamethasone, andprednisolone), hormonal agents (e.g., tamoxifen, raloxifene, leuprolide,bicaluatmide, granisetron, and flutamide), aromatase inhibitors (e.g.,letrozole and anastrozole), arsenic trioxide, tretinoin, nonselectivecyclooxygenase inhibitors (e.g., nonsteroidal anti-inflammatory agents,salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn,diclofenac, tolmetin, ketoprofen, nabumetone, and oxaprozin), selectivecyclooxygenase-2 (COX-2) inhibitors, or any combination thereof.

Examples of biological agents that can be used in the compositions andmethods described herein include monoclonal antibodies (e.g., rituximab,cetuximab, panetumumab, tositumomab, trastuzumab, alemtuzumab,gemtuzumab ozogamicin, bevacizumab, catumaxomab, denosumab,obinutuzumab, ofatumumab, ramucirumab, pertuzumab, ipilimumab,nivolumab, nimotuzumab, lambrolizumab, pidilizumab, siltuximab,BMS-936559, RG7446/MPDL3280A, MED14736, tremelimumab, or others known inthe art), enzymes (e.g., L-asparaginase), cytokines (e.g., interferonsand interleukins), growth factors (e.g., colony stimulating factors anderythropoietin), cancer vaccines, gene therapy vectors, or anycombination thereof.

In some embodiments, compounds of the present disclosure is administeredto a subject in need thereof in combination with another agent for thetreatment of cancer, either in the same or in different pharmaceuticalcompositions. In some embodiments, the additional agent is an anticanceragent. In some embodiments, the additional agent affects (e.g.,inhibits) histone modifications, such as histone acetylation or histonemethylation. In certain embodiments, an additional anticancer agent isselected from the group consisting of chemotherapeutics (such as 2CdA,5-FU, 6-Mercaptopurine, 6-TG, Abraxane™, Accutane®, Actinomycin-D,Adriamycin®, Alimta®, all-trans retinoic acid, amethopterin, Ara-C,Azacitadine, BCNU, Blenoxane®, Camptosar®, CeeNU®, Clofarabine, Clolar™,Cytoxan®, daunorubicin hydrochloride, DaunoXome®, Dacogen®, DIC, Doxil®,Ellence®, Eloxatin®, Emcyt®, etoposide phosphate, Fludara®, FUDR®,Gemzar®, Gleevec®, hexamethylmelamine, Hycamtin®, Hydrea®, Idamycin®,Ifex®, ixabepilone, Ixempra®, L-asparaginase, Leukeran®, liposomalAra-C, L-PAM, Lysodren, Matulane®, mithracin, Mitomycin-C, Myleran®,Navelbine®, Neutrexin®, nilotinib, Nipent®, Nitrogen Mustard,Novantrone®, Oncaspar®, Panretin®, Paraplatin®, Platinol®,prolifeprospan 20 with carmustine implant, Sandostatin®, Targretin®,Tasigna®, Taxotere®, Temodar®, TESPA, Trisenox®, Valstar®, Velban®,Vidaza™, vincristine sulfate, VM 26, Xeloda® and Zanosar®); biologics(such as Alpha Interferon, Bacillus Calmette-Guerin, Bexxar®, Campath®,Ergamisol®, Erlotinib, Herceptin®, Interleukin-2, Iressa®, lenalidomide,Mylotarg®, Ontak®, Pegasys®, Revlimid®, Rituxan®, Tarceva™, Thalomid®,Velcade® and Zevalin™); small molecules (such as Tykerb®);corticosteroids (such as dexamethasone sodium phosphate, DeltaSone® andDelta-Cortef®); hormonal therapies (such as Arimidex®, Aromasin®,Casodex®, Cytadren®, Eligard®, Eulexin®, Evista®, Faslodex®, Femara®,Halotestin®, Megace®, Nilandron®, Nolvadex®, Plenaxis™ and Zoladex®);and radiopharmaceuticals (such as Iodotope®, Metastron®, Phosphocol® andSamarium SM-153).

The additional agents that can be used in combination with compounds ofthe present disclosure as set forth above are for illustrative purposesand not intended to be limiting. The combinations embraced by thisdisclosure, include, without limitation, one or more compounds of thepresent disclosure as provided herein and at least one additional agentselected from the lists above or otherwise provided herein. Compounds ofthe present disclosure can also be used in combination with one or withmore than one additional agent, e.g., with two, three, four, five, orsix, or more, additional agents.

In some embodiments, treatment methods described herein are performed onsubjects for which other treatments of the medical condition have failedor have had less success in treatment through other means, e.g., insubjects having a cancer refractory to standard-of-care treatment.Additionally, the treatment methods described herein can be performed inconjunction with one or more additional treatments of the medicalcondition, e.g., in addition to or in combination with standard-of-caretreatment. For instance, the method can comprise administering acancer-therapeutic regimen, e.g., nonmyeloablative chemotherapy,surgery, hormone therapy, and/or radiation, prior to, substantiallysimultaneously with, or after the administration of compounds of thepresent disclosure described herein, or composition thereof. In certainembodiments, a subject to which compounds of the present disclosuredescribed herein is administered can also be treated with antibioticsand/or one or more additional pharmaceutical agents.

EXAMPLES Synthetic Procedures

Materials and Methods

Equipment: ¹H NMR Spectra were recorded at 400 MHz using a Bruker AVANCE400 MHz spectrometer. LC-MS equipment and conditions are as follows:

LC-MS (Agilent):

LC: Agilent Technologies 1290 series, Binary Pump, Diode Array Detector.Agilent Poroshell 120 EC-C18, 2.7 μm, 4.6×50 mm column. Mobile phase: A:0.05% Formic acid in water (v/v), B: 0.05% Formic acid in ACN (v/v).Flow Rate: 1 mL/min at 25° C. Detector: 214 nm, 254 nm. Gradient stoptime, 5 min. Timetable:

T (min) A(%) B(%) 0.0 90 10 0.5 90 10 4.5 0 100 4.51 90 10 5.0 90 10

MS: G6120A, Quadrupole LC/MS, Ion Source: ES-API, TIC: 70˜1000 m/z,Fragmentor: 60, Drying gas flow: 10 L/min, Nebulizer pressure: 35 psi,Drying gas temperature: 350° C., Vcap: 3000V.

Sample preparation: samples were dissolved in ACN or methanol at ˜100μg/mL, then filtered through a 0.22 μm filter membrane. Injectionvolume: 110 μL.

Definitions: Boc (tert-butoxycarbonyl); CDCl₃ (deuterated chloroform);DCM (dichloromethane); DMF (N,N-dimethylformamide); DMSO(dimethylsulfoxide); DMSO-d₆ (deuterated dimethylsulfoxide); EDCI(1-ethyl-3-(3-dimethylaminopropyl) carbodiimide); eq (equivalent);ES-API (electrospray atmospheric pressure ionization); Et₃N(triethylamine); Et₂O (diethyl ether); EtOAc (ethyl acetate); g (gram);h (hour); HATU(2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate); ¹H NMR (proton nuclear magnetic resonance); HOBt(hydroxybenzotriazole); Hz (hertz); L (litre); LC-MS (liquidchromatography-mass spectrometry); M (molar); MeOH (methanol); mg(milligrams); MHz (megahertz); min (minutes); mL (millilitres), mmol(millimoles); Pet. ether (petroleum ether); ppm (parts per million); psi(pounds per square inch); R_(t) (retention time); RT (room temperature);THF (tetrahydrofuran); TLC (thin layer chromatography); v/v(volume/volume).

Common Intermediate

Step 1: 4-iodo-1-methyl-1H-imidazole

Sodium hydride (15.3 g, 385 mmol) was added to a mixture of4-iodo-1H-imidazole (50 g, 257 mmol) in THF (150 mL) at 0° C. Afterstirring for 0.5 h, iodomethane (40.0 g, 282 mmol) was added to thesolution and the resulting mixture was stirred at room temperatureovernight under N₂. TLC (DCM/EtOAc=2/1, v/v) indicated that startingmaterial was consumed and two new spots were formed. The reaction wasquenched with MeOH (50 mL), then concentrated to dryness, the residuewas purified by silica gel column (DCM/EtOAc=10/1, v/v) to afford thedesired product (higher Rf) (28 g, 52%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.32 (s, 1H), 6.96 (d, J=1.2 Hz, 1H),3.68 (s, 3H).

Step 2: 1-methyl-4-(tributylstannyl)-1H-imidazole

To a solution of 4-iodo-1-methyl-1H-imidazole (34.0 g, 163 mmol) in THF(300 mL) at −10° C. was added isopropylmagnesium chloride (25.0 g, 244mmol) dropwise under N₂. The mixture was stirred for 1 h at thistemperature, and then tributylchlorostannane (55.6 g, 171 mmol) wasadded drop-wise. The reaction was stirred at room temperature overnightunder N₂. The reaction mixture was diluted with saturated aqueous NH₄Cl(400 mL) and extracted with EtOAc (200 mL×3). The combined organicphases were washed with water (200 mL×2) and brine (200 mL), dried overNa₂SO₄, and concentrated to dryness, to afford the desired product (65.0g, 100%) as colourless oil, which was used in the next step directly.

LC-MS (Agilent): R_(t) 2.84 min; m/z calculated for C₁₆H₃₂N₂Sn [M+H]⁺373.2, found 373.2

Step 3: 5-bromo-3-chloro-2-fluorobenzoic acid

To a solution of 3-chloro-2-fluorobenzoic acid (80 g, 458 mmol) in 98%conc. H₂SO₄ (400 mL) was added 1-bromopyrrolidine-2,5-dione (85.4 g, 480mmol) at 0° C. The mixture was stirred at 0° C. for 3 h under N₂, thenwarmed to room temperature and stirred for 28 h. The mixture was pouredinto ice-water (1000 mL), and the solid was collected by filtration,washed with water and dried to afford the desired product (110 g, 91%)as a white solid.

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.11-8.05 (m, 1H), 7.90-7.87 (m, 1H).

Step 4: methyl 5-bromo-3-chloro-2-fluorobenzoate

To a solution of 5-bromo-3-chloro-2-fluorobenzoic acid (50.4 g, 198mmol) in MeOH (400 mL) was added SOCl₂ (40 mL) slowly at 0° C. Thereaction solution was heated at reflux for 4 h under N₂. The reactionmixture was concentrated in vacuo to give a white solid. The solid wasdiluted with EtOAc (500 mL) and the solution was washed with water (250mL), Sat. NaHCO₃ (200 mL, aq), and brine (250 mL) and concentrated invacuo to afford the desired product (51 g, 96%) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.21-8.18 (m, 1H), 7.96-7.93 (m, 1H),3.88 (s, 3H).

Step 5: methyl 3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoate

A mixture of 1-methyl-4-(tributylstannyl)-1H-imidazole (60.6 g, 163mmol), methyl 5-bromo-3-chloro-2-fluorobenzoate (33.4 g, 125 mmol) andpotassium fluoride (28.4 g, 489 mmol) in toluene (600 mL) was degassedwith N₂ and tetrakis(triphenylphosphane) palladium (2.81 g, 2.44 mmol)was added quickly. The reaction mixture was heated to 100° C. andstirring continued overnight. The reaction mixture was cooled to roomtemperature, potassium fluoride (28.4 g, 489 mmol) and water (300 mL)were added and the mixture stirred for a further 30 min. The mixture wasdiluted with EtOAc (500 mL) and filtered. The organic layer wasseparated and the aqueous layer extracted with EtOAc (200 mL×2). Theorganic phases were combined and dried over Na₂SO₄, concentrated todryness, to afford the crude product, which was triturated with(Petroleum/EtOAc=10/1, v/v) to afford the desired product (33.5 g, 77%)as an off-white solid.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.12 (dd, J=6.0, 2.3 Hz, 1H), 8.04 (dd,J=6.4, 2.3 Hz, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 3.95 (s, 3H), 3.75 (s,3H).

Step 6: 3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoic acid

To a solution of sodium hydroxide (19.9 g, 500 mmol) in water (200 mL)was added a solution of methyl3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoate (33.8 g, 125mmol) in THF (250 mL) drop-wise. After the addition was complete, thereaction was stirred for further 2 h at room temperature. Most of thesolvent was removed by evaporation, and the residue was adjusted pH to5.0 with HCl (6.0 M, aq). The mixture was stirred for 30 min and thesolid was collected by filtration, washed with small amount of DCM (20mL×2) and dried in vacuo to afford the desired product (29.2 g, 92%) asan off-white solid.

¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.14 (dd, J=6.4, 2.3 Hz, 1H), 8.07(dd, J=6.5, 2.3 Hz, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 3.68 (s, 3H).

Compound I-51

Step 1: cyclohexylmethyl methanesulfonate

Methanesulfonyl chloride (65.0 g, 568 mmol) was added to a solution ofcyclohexylmethanol (50 g, 437 mmol) and triethylamine (66.2 g, 655 mmol)in DCM (600 mL) at 0° C. under N₂. After stirring at room temperaturefor 6 h, the reaction mixture was washed with 1 M HCl (150 mL) and theaqueous layer was extracted with DCM (200 mL×2). The combined organiclayers were dried over Na₂SO₄ and concentrated to afford the desiredproduct (84 g, 99%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 4.01 (d, J=6.0 Hz, 2H), 2.99 (s, 3H),1.76-1.65 (m, 6H), 1.30-1.14 (m, 3H), 1.04-0.98 (m, 2H)

Step 2: S-(cyclohexylmethyl) ethanethioate

Potassium thioacetate (59.7 g, 523 mmol) was added to a solution ofcyclohexylmethyl methanesulfonate (84 g, 436 mmol) in DMF (800 mL) underN₂. After heating at 60° C. for 5 h, the reaction mixture was dilutedwith H₂O (6 L) and extracted with EtOAc (2 L×2). The combined organiclayers were washed with brine (1 L), dried over Na₂SO₄ and concentrated.The residue was purified by silica gel column (PE/EtOAc=15/1, v/v) toafford the desired product (57 g, 76%) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 2.78 (d, J=6.8 Hz, 2H), 2.32 (s, 3H),1.78-1.62 (m, 5H), 1.45-1.41 (m, 1H), 1.30-1.20 (m, 3H), 0.98-0.92 (m,2H)

Step 3: cyclohexylmethanesulfonyl chloride

2 M Hydrochloric acid (178 mL, 357 mmol) was added to a solution ofN-chlorosuccinimide (173 g, 1300 mmol) in acetonitrile (1 L) at 0° C.under N₂, S-(cyclohexylmethyl) ethanethioate (56 g, 325 mmol) was addedand the reaction was stirred at room temperature overnight. The reactionmixture was concentrated in vacuo and the residue was extracted withEtOAc (500 mL×2). The combined organic layers were dried over Na₂SO₄ andconcentrated to afford the desired product (63.9 g, 100%) as colourlessoil, which was used to the next step directly.

Step 4: cyclohexylmethanesulfonohydrazide

80% hydrazine hydrate (46.5 g, 745 mmol) was added to a solution ofcyclohexylmethanesulfonyl chloride (63.9 g, 324 mmol) in THE (1 L) at 0°C. After stirring at room temperature for 1 hour, the reaction mixturewas concentrated and the residue purified by silica gel column(DCM/MeOH=20/1, v/v) to afford the desired product (17 g, 27%) as awhite solid.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.78 (s, 1H), 4.31 (s, 2H), 2.93 (d,J=5.2 Hz, 2H), 1.87-1.77 (m, 3H), 1.66-1.57 (m, 3H), 1.24-1.02 (m, 5H)

Step 5:N′-(3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoyl)-1-cyclohexylmethanesulfonohydrazide

To a solution of 3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoicacid (250.0 mg, 0.98 mmol) in toluene (10 mL) was added oxalyl chloride(374.0 mg, 2.95 mmol) and DMF (cat.) at room temperature under N₂. Thereaction was heated at 60° C. for 1 h, then concentrated under reducedpressure and the residue dissolved in dichloromethane (15 mL). To thissolution was added sodium carbonate (312.3 mg, 2.95 mmol) andcyclohexylmethanesulfonohydrazide (188.8 mg, 0.98 mmol). The resultingmixture was stirred at room temperature overnight. Methanol (5 mL) wasadded and the mixture concentrated under reduced pressure. The residuewas purified by silica gel column (DCM/MeOH=20/1, v/v) to afford thedesired product (140 mg, 31%) as a white solid.

LC-MS (Agilent): R_(t) 2.73 min; m/z calculated for C₁₈H₂₂ClFN₄O₃S[M+H]⁺ 429.0/431.1, found 429.0/431.1.

¹H NMR (400 MHz, d₆-DMSO) δ (ppm): 10.71 (brs, 1H), 9.73 (brs, 1H), 8.03(dd, J=6.4, 1.6 Hz 1H), 7.84 (dd, J=5.6, 2.0 Hz 1H), 7.78 (s, 1H), 7.69(s, 1H), 3.69 (s, 3H), 3.03 (d, J=6.4 Hz, 2H), 2.02-1.94 (m, 1H),1.91-1.88 (m, 2H), 1.68-1.58 (m, 3H), 1.29-1.02 (m, 5H).

Compound I-315

Step 1: 4-methoxybenzene-1-sulfonohydrazide

80% Hydrazine hydrate (693 mg, 11.1 mmol) was added into a solution of4-methoxybenzene-1-sulfonyl chloride (1 g, 4.83 mmol) in THF (20 mL) at0° C. under N₂, then the mixture stirred at room temperature for 30 min.The reaction solution was filtered, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel column(DCM/MeOH=20/1, v/v) to afford the desired product (825 mg, 84%) as awhite solid.

LC-MS (Agilent): R_(t) 1.82 min; m/z calculated for C₇H₁₀N₂O₃S[M+1]⁺=203.1, found 203.1.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.19 (t, J=3 Hz, 1H), 7.72 (d, J=8.8Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 4.01 (d, J=3.2 Hz, 3H), 3.84 (s, 3H).

Step 2:N′-(3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoyl)-4-methoxybenzenesulfonohydrazide

To a solution of 3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoicacid (100 mg, 395 μmol) in toluene (20 mL) were added oxalyl chloride(200 mg, 1.58 mmol) and DMF (Cat.). After stirring at 60° C. for 2 h,the reaction mixture was concentrated in vacuo. The residue obtained wasdissolved in dichloromethane (20 mL) and to this solution were added4-methoxybenzene-1-sulfonohydrazide (80 mg, 395 μmol) and sodiumcarbonate (146 mg, 1.38 mmol). The reaction was stirred at roomtemperature for 16 h under N₂. The reaction solution was filtered andthe filtrate concentrated under reduced pressure. The residue waspurified by column (DCM/MeOH=20/1, v/v) to afford the desired product(80 mg, 46%) as a white solid.

LC-MS (Agilent): R_(t) 2.24 min; m/z calculated for C₁₈H₁₆ClFN₄O₄S[M+1]⁺=439.1/441.1, found 439.1/441.1.

¹H NMR: (400 MHz, DMSO-d₆) δ (ppm): 10.69 (d, J=3.2 Hz, 1H), 10.02 (d,J=3.6 Hz, 1H), 7.98 (dd, J=6.4, 1.6 Hz, 1H), 7.80 (d, J=8.8 Hz, 2H),7.75 (s, 1H), 7.68-7.65 (m, 2H), 7.10 (d, J=8.8 Hz, 2H), 3.83 (s, 3H),3.69 (s, 3H).

Compound I-344

Step 1: tert-butyl (3-bromophenyl)carbamate

A solution of 3-bromoaniline (5.0 g, 29.0 mmol) and di-tert-butyldicarbonate (9.49 g, 43.5 mmol) in sodium hydroxide solution (2 M, 100mL) was stirred at 90° C. for 1 h. After cooling to room temperature,the reaction was diluted with water (100 mL) and extracted with EtOAc(50 mL×2). The combined organic phases were washed with brine (100 mL),dried over Na₂SO₄ and concentrated to afford the desired product (7.89g, 100%) as a white solid.

LC-MS (Agilent): R_(t) 4.00 min; m/z calculated for C₁₁H₁₄BrNO₂[M−56+H]⁻ 216.0, found 216.0.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.66 (s, 1H), 7.21-7.19 (m, 1H),7.17-7.11 (m, 2H), 6.48 (brs, 1H), 1.52 (s, 9H).

Step 2: tert-butyl (3-bromophenyl)(methyl)carbamate

Sodium hydride (806 mg, 20.2 mmol) was added to a solution of tert-butylN-(3-bromophenyl)carbamate (3.7 g, 13.5 mmol) in DMF (80 mL) at 0° C.After stirring for 0.5 h under N₂, iodomethane (2.10 g, 14.8 mmol) wasadded and the resulting reaction was stirred at room temperatureovernight under N₂. The mixture was poured into water (100 mL) andextracted with EtOAc (50 mL×2). The combined organic phases were washedwith water (100 mL×3), brine (100 mL), dried over Na₂SO₄ andconcentrated to afford the desired product (3.86 g, 100%) as a yellowoil.

LC-MS (Agilent): R_(t) 4.18 min; m/z calculated for C₁₂H₁₆BrNO₂[M−56+H]⁻ 230.0, found 230.0.

1H NMR (400 MHz, CDCl₃) δ (ppm): 7.42 (s, 1H), 7.30-7.27 (m, 1H), 7.18(d, J=4.8 Hz, 2H), 3.24 (s, 3H), 1.46 (s, 9H).

Step 3: tert-butyl (3-(benzylthio)phenyl)(methyl)carbamate

To a mixture of tert-butyl N-(3-bromophenyl)-N-methylcarbamate (1.5 g,5.24 mmol) in dioxane (50.0 mL) were added Pd₂(dba)₃ (479 mg, 524 μmol),Xantphos (601 mg, 1.04 mmol), phenylmethanethiol (976 mg, 7.86 mmol) andDIEA (1.34 g, 10.4 mmol). The mixture was stirred at reflux under a N₂atmosphere overnight. The reaction mixture was diluted with water (100mL) and extracted with EtOAc (60 mL×3). The combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel column (Pet.ether/EtOAc=50/1, v/v) to affordthe desired product (1.7 g, 99%) as a red oil.

LC-MS (Agilent): R_(t) 4.45 min; m/z calculated for C₁₉H₂₃NO₂S [M−56+H]⁺274.1, found 274.1.

¹H NMR (400 MHz, d₆-DMSO) δ (ppm): 7.36-7.34 (m, 2H), 7.29 (s, 1H),7.27-7.26 (m, 1H), 7.24 (s, 1H) 7.22-7.21 (m, 2H), 7.13-7.11 (m, 1H),7.08-7.06 (m, 1H), 4.24 (s, 2H), 3.12 (s, 3H), 1.37 (s, 9H).

Step 4: tert-butyl (3-(chlorosulfonyl)phenyl)(methyl)carbamate

2 M Hydrochloric acid (235 mg, 6.46 mmol) was added to a solution ofN-chlorosuccinimide (3.13 g, 23.5 mmol) in acetonitrile (10.0 mL) at 0°C. After stirring 10 min at 0° C. under N₂, tert-butyl(3-(benzylthio)phenyl)(methyl)carbamate (1.94 g, 5.88 mmol) was addedand the mixture was stirred at room temperature for 20 min. The reactionmixture was concentrated in vacuo, the residue was diluted with water(50 mL) and extracted with EtOAc (50 mL×3). The combined organic layerswere dried over Na₂SO₄ and concentrated to give the crude product (1.79g, 100%) as a yellow oil, which was used for the next step directly.

Step 5: tert-butyl (3-(hydrazinylsulfonyl)phenyl)(methyl)carbamate

80% Hydrazine hydrate (837 mg, 13.4 mmol) was added to a solution oftert-butyl N-[3-(chlorosulfonyl)phenyl]-N-methylcarbamate (1.79 g, 5.85mmol) in THF (25 mL) at 0° C. under N₂ atmosphere, then the mixture wasstirred at room temperature for 20 min. The mixture was concentrated andthe residue was purified by column (DCM:MeOH=80:1) to give the desiredproduct (1.12 g, ˜60% purity by LCMS, 64%) as a yellow oil.

LC-MS (Agilent): R_(t) 2.76 min; m/z calculated for C₁₂H₁₉N₃O₄S[M−56+H]⁺ 246.1, found 246.1.

Step 6:tert-butyl(3-((2-(3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoyl)hydrazinyl)sulfonyl)phenyl)(methyl)carbamate

To a solution of 3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoicacid (211 mg, 0.8295 mmol) in toluene (20 mL) were added oxalyl chloride(314 mg, 2.48 mmol) and DMF (Cat.). After stirring at 60° C. for 2 h,the reaction mixture was concentrated in vacuo. The residue obtained wasdissolved in dichloromethane (20 mL) and to this solution were addedtert-butyl N-[3-(hydrazinesulfonyl)phenyl]-N-methylcarbamate (250 mg,0.83 mmol) and sodium carbonate (262 mg, 2.48 mmol). The reaction wasstirred at room temperature for 12 h under N₂. The reaction solution wasfiltered and the filtrate concentrated in vacuo. The residue waspurified by silica gel column (DCM/MeOH=40/1, v/v) then reverse phasecolumn (C18 column, 40 g, 45% ACN in water) to afford the desiredproduct (110 mg, 25%) as a white solid.

LC-MS (Agilent): R_(t) 2.72 min; m/z calculated for C₂₃H₂₅ClFNSO₅S[M−56+H]⁺ 538.1/540.1, found 538.1/540.1.

¹H NMR (400 MHz, d₆-DMSO) δ (ppm): 10.74 (s, 1H), 10.26 (s, 1H), 7.99(dd, J=6.8, 2.0 Hz, 1H), 7.82 (s, 1H), 7.74 (s, 1H), 7.70-7.66 (m, 3H),7.58-7.54 (m, 2H), 3.68 (s, 3H), 3.19 (s, 3H), 1.37 (s, 9H).

Step 7:N′-(3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoyl)-3-(methylamino)benzenesulfonohydrazide Hydrochloride

A solution of tert-butylN-[3-({[3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)phenyl]formohydrazido}sulfonyl)phenyl]-N-methylcarbamate(95 mg, 0.18 mmol) in 1 M HCl/EtOAc (642 mg, 17.6 mmol) was stirred atroom temperature overnight under N₂. The mixture was filtered, and thefilter cake was washed with EtOAc (2 mL) to give the desired product (78mg, 87%) as a white solid.

LC-MS (Agilent): R_(t) 2.14 min; m/z calculated for C₁₈H₁₇ClFN₅O₃S[M+H]⁺ 438.1/440.1, found 438.1/440.1.

¹H NMR (400 MHz, d₆-DMSO) δ (ppm): 10.70 (s, 1H), 10.11 (s, 1H), 9.22(s, 1H), 8.33 (dd, J=6.4, 2.0 Hz, 1H), 8.30 (s, 1H), 7.86-7.84 (dd,J=5.2, 2.0 Hz, 1H), 7.31 (t, J=8.2 Hz, 1H), 7.16 (s, 2H), 6.90 (d, J=7.6Hz, 1H), 3.89 (s, 3H), 2.71 (s, 3H).

Compound I-318

Step 1: 2-fluorobenzenesulfonohydrazide

To a solution of 2-fluorobenzenesulfonohydrazide (2.0 g, 10.3 mmol) inTHF (40 mL) was added dropwise 80% hydrazine hydrate (1.48 g, 23.7 mmol)at 0° C. under a nitrogen atmosphere. The resulting mixture was stirredat 0° C. for 30 min. The reaction mixture was concentrated in vacuo andthe residue purified by silica gel column (DCM/MeOH=50/1, v/v) to affordthe desired product (1.5 g, 77%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.63 (s, 1H), 7.80 (td, J=7.6 Hz, 1.6Hz, 11H), 7.74-7.68 (m, 11H), 7.44-7.36 (m, 2H), 4.29 (brs, 2H).

Step 2:N′-(3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoyl)-2-fluorobenzenesulfonohydrazide

3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl) benzoic acid (100 mg,0.39 mmol) was dissolved in toluene (5 mL), oxalyl chloride (125 mg.0.98 mmol) and DMF (cat) were added. After stirring at 60° C. for 1 hunder nitrogen atmosphere, toluene was removed under reduced pressure.The residue was dissolved in DCM (5 mL) and this solution was added to asuspension of 2-fluorobenzenesulfonohydrazide (74 mg, 0.39 mmol) andsodium carbonate (124 mg, 1.17 mmol) in DCM (5 mL). After stirring atroom temperature overnight under a nitrogen atmosphere, the reactionmixture was concentrated and the residue was purified by silica gelcolumn (DCM/MeOH=40/1, v/v) to give the desired product (60 mg, 36%) asa white solid.

LC-MS (Agilent): R_(t) 2.20 min; m/z calculated for C₁₇H₁₃ClF₂N₄O₃S[M+H]⁺ 427, found 427.0.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.78 (d, J=2.8 Hz, 1H), 10.48 (d,J=2.8 Hz, 1H), 7.99 (dd, J=6.8, 2.4 Hz, 1H), 7.85 (td, J=7.6 Hz, 1.2 Hz,1H), 7.74-7.66 (m, 4H), 7.41 (t, J=10.4 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H),3.69 (s, 3H).

Compound I-386

Step 1: 2-bromo-5-methoxypyridine

A mixture of 2-bromo-5-methoxypyridine (1 g, 5.31 mmol), BnSH (988 mg,7.96 mmol), DIEA (1.36 g, 10.6 mmol), Pd₂(dba)₃ (243 mg, 0.266 mmol) andXantphos (307 mg, 0.531 mmol) in 1,4-Dioxane (10 mL) was heated atreflux overnight. The reaction solution was concentrated and the residuewas purified by silica gel column (PE:EtOAc=20:1) to afford the desiredproduct (1.17 g, 96%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.22 (d, J=2.8 Hz, 1H), 7.37-7.33 (m,2H), 7.32-7.21 (m, 5H), 4.35 (s, 2H), 3.79 (s, 3H).

Step 2: 5-methoxypyridine-2-sulfonyl chloride

To a solution of NCS (1.15 g, 8.64 mmol) in MeCN (10 mL) was added HCl(84.1 mg, 2.37 mmol) at 0° C. and the solution was stirred for 10 min.2-(benzylsulfanyl)-5-methoxypyridine (500 mg, 2.16 mmol) was added andthe resulting mixture was stirred for 30 min. The reaction solution wasdiluted with water (60 mL) and extracted with EtOAc (20 mL×3). Thecombined organic phases were dried over Na₂SO₄ and concentrated to give5-methoxypyridine-2-sulfonyl chloride (1.5 g) as a brown oil, which wasused in the next step directly.

Step 3: 5-methoxypyridine-2-sulfonohydrazide

To a solution of 5-methoxypyridine-2-sulfonyl chloride (448 mg, 2.15mmol) in THF (10 mL) was added hydrazine hydrate (308 mg, 4.94 mmol) at0° C. and the resulting mixture was stirred for 1 h. The mixture wasconcentrated under reduced pressure and the residue purified by silicagel column (DCM:MeOH=20:1, v/v) to afford the desired product (165 mg,38%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.56 (s, 1H), 8.41 (d, J=2.81 Hz,1H), 7.91 (d, J=8.8 Hz, 1H), 7.61 (dd, J=6.0, 2.8 Hz, 1H), 4.14 (s, 2H),3.92 (s, 3H).

Step 4:N′-(3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoyl)-5-methoxypyridine-2-sulfonohydrazide

To a solution of 3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoicacid (150 mg, 0.59 mmol) in toluene (5 mL) were added oxalyl chloride(223 mg, 1.76 mmol) and DMF (cat.), the mixture was stirred at 60° C.for 1 h. The reaction mixture was concentrated in vacuo and the residueobtained was dissolved in DCM (5.0 mL). This solution was added into asuspension of 5-methoxypyridine-2-sulfonohydrazide (119 mg, 0.589 mmol)and sodium carbonate (124 mg, 1.17 mmol) in DCM (5.0 mL). The reactionmixture was stirred at room temperature overnight and then concentratedin vacuo. The residue was purified by silica gel column (DCM/MeOH=20/1,v/v) to afford the desired product (150 mg, 54%) as a white solid.

LC-MS (Agilent): R_(t) 1.94 min; m/z calculated for C₁₇H₁₅ClFN₅O₄S[M+1]⁺=439.85, found 440.1/442.1.

¹H NMR: (400 MHz, DMSO-d₆) δ (ppm): 10.65 (s, 1H), 10.24 (s, 1H), 8.41(d, J=2.8 Hz, 1H), 7.98 (dd, J=6.8, 2.0 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H),7.76 (s, 1H), 7.71-7.69 (m, 2H), 7.59 (dd, J=8.4, 2.8 Hz, 1H), 3.91 (s,3H), 3.68 (s, 3H).

Compound I-376

Step 1: benzyl(2-fluoro-4-methoxyphenyl)sulfane

To a solution of 1-bromo-2-fluoro-4-methoxybenzene (1.0 g, 4.88 mmol)and phenylmethanethiol (909 mg, 7.32 mmol) in 1,4-dioxane (30 mL) wereadded Pd₂(dba)₃ (445 mg, 0.49 mmol), Xantphos (564 mg, 0.97 mmol) andDIPEA (1.25 g, 9.74 mmol), the resulting mixture was stirred at refluxunder N₂ atmosphere overnight. The mixture was diluted with EtOAc (50mL) and washed with water. The organic layer was dried and concentrated,the residue was purified by column (pet.ether) to afford the desiredproduct (1.1 g, 92%) as a yellow oil.

LC-MS (Agilent): R_(t) 3.00 min; m/z calculated for C₁₄H₁₃FOS [M+1]⁺249.1, found 249.1.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.27 (s, 1H), 7.25-7.14 (m, 5H), 6.65(dd, J=10.8, 2.4 Hz, 1H), 6.57 (dd, J=8.8, 2.4 Hz, 1H), 3.98 (s, 2H),3.79 (s, ³H)

Step 2: 2-fluoro-4-methoxybenzenesulfonohydrazide

To a solution of N-chlorosuccinimide (1.07 g, 8.04 mmol) in MeCN (5 mL)was added hydrochloric acid (2 M, 80.5 mg, 2.21 mmol) at 0° C., themixture was stirred at 0° C. for 20 min.1-(benzylsulfanyl)-2-fluoro-4-methoxybenzene (500 mg, 2.01 mmol) in MeCN(2 mL) was added and the mixture was stirred at room temperature for 0.5h. The mixture was concentrated to afford the crude product. The crudeproduct dissolved in THF was added into a solution of hydrazine hydrate(333 mg, 5.34 mmol) in THF (8 mL) slowly at 0° C. and the resultingmixture was stirred at RT for 1 h. The mixture was concentrated and theresidue was purified by silica gel column (DCM:MeOH=20:1) to afford thedesired product (210 mg, 47%) as a colourless oil.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.44 (s, 1H), 7.69 (t, J=8.4 MHz,1H), 7.03 (d, J=12.4 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.19 (s, 2H), 3.85(s, 3H).

Step 3:N′-(3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoyl)-2-fluoro-4-methoxybenzenesulfonohydrazide

To a solution of 3-chloro-2-fluoro-5-(1-methyl-1H-imidazol-4-yl)benzoicacid (115 mg, 0.454 mmol) in toluene (5 mL) were added oxalyl chloride(172 mg, 1.36 mmol) and DMF (cat.). The mixture was stirred at 60° C.for 1 h then concentrated and the residue was added to a mixture of2-fluoro-4-methoxybenzene-1-sulfonohydrazide (100 mg, 0.454 mmol) andsodium carbonate (96.2 mg, 0.908 mmol) in DCM (5 mL). The resultingmixture was stirred at room temperature overnight. The mixture wasconcentrated and the residue was purified by reverse phase column (C18column, 40 g, 60% ACN in water) to afford the desired product (45 mg,22%) as a light yellow solid.

LC-MS (Agilent): R_(t) 2.29 min; m/z calculated for C₁₈H₁₅ClF₂N₄O₄S[M+1]⁺ 457.1/459.1, found 457.1/459.1.

¹H NMR: (400 MHz, DMSO-d6) δ (ppm): 10.72 (s, 1H), 10.29 (s, 1H), 7.98(s, 1H), 7.80-7.60 (m, 4H), 7.06-6.97 (m, 1H), 6.92-6.88 (m, 1H), 3.83(s, 3H), 3.68 (s, 3H).

Biochemical Assays

KAT-5. Enzyme assay buffer was 50 mM Tris pH 8.0, 0.002% Tween20, 0.005%bovine skin gelatin, and 1 mM dithiothreitol (DTT). For determination ofIC₅₀ values, compounds were serially diluted with 2% (v/v) DMSO in thefinal reaction, pre-incubating each dilution of each compound with 40 μLof assay buffer containing KAT-5 enzyme (9 nM final concentration). 10μL of assay buffer containing 1 μM peptide substrate and 0.5 μM acetylcoenzyme A (final concentrations) was added. Reactions (50 μL total)were then carried out at 25° C. for 90 minutes. Reactions wereterminated by the addition of 0.5% formic acid (final concentration),and a sample of each reaction was analyzed by SAMDI Tech, Inc. (Chicago,IL) using self-assembled monolayer desorption/ionization time-of-flightmass spectrometry (Mrksich, M. (2008) Mass spectrometry ofself-assembled monolayers: a new tool for molecular surface science. ACSNano 2, 7-18).

KAT-6A. Enzyme assay buffer was 50 mM Tris pH 8.0, 0.002% Tween20,0.005% bovine skin gelatin, and 1 mM dithiothreitol (DTT). Fordetermination of IC₅₀ values, compounds were serially diluted with 2%(v/v) DMSO in the final reaction, pre-incubating each dilution of eachcompound with 40 μL of assay buffer containing KAT-6A enzyme (12.5 nMfinal concentration). 10 μL of assay buffer containing 1 μM peptidesubstrate and 1 μM acetyl coenzyme A (final concentrations) was added.Reactions (50 μL total) were then carried out at 25° C. for 90 minutes.Reactions were terminated by the addition of 0.5% formic acid (finalconcentration), and a sample of each reaction was analyzed by SAMDITech, Inc. (Chicago, IL) using self-assembled monolayerdesorption/ionization time-of-flight mass spectrometry (Mrksich, M.(2008) Mass spectrometry of self-assembled monolayers: a new tool formolecular surface science. ACS Nano 2, 7-18).

KAT-7. Enzyme assay buffer was 50 mM Tris pH 8.0, 0.002% Tween20, 0.005%bovine skin gelatin, and 1 mM dithiothreitol (DTT). For determination ofIC₅₀ values, compounds were serially diluted with 2% (v/v) DMSO in thefinal reaction, pre-incubating each dilution of each compound with 40 μLof assay buffer containing KAT-7 enzyme (6 nM final concentration). 10μL of assay buffer containing 1 μM peptide substrate and 2 μM acetylcoenzyme A (final concentrations) was added. Reactions (50 μL total)were then carried out at 25° C. for 120 minutes. Reactions wereterminated by the addition of 0.5% formic acid (final concentration),and a sample of each reaction was analyzed by SAMDI Tech, Inc. (Chicago,IL) using self-assembled monolayer desorption/ionization time-of-flightmass spectrometry (Mrksich, M. (2008) Mass spectrometry ofself-assembled monolayers: a new tool for molecular surface science. ACSNano 2, 7-18).

KA T-8. Enzyme assay buffer was 50 mM Tris pH 8.0, 0.002% Tween20,0.005% bovine skin gelatin, and 1 mM dithiothreitol (DTT). Fordetermination of IC₅₀ values, compounds were serially diluted with 2%(v/v) DMSO in the final reaction, pre-incubating each dilution of eachcompound with 40 μL of assay buffer containing KAT-8 enzyme (12.5 nMfinal concentration). 10 μL of assay buffer containing 1 μM peptidesubstrate and 5 μM acetyl coenzyme A (final concentrations) was added.Reactions (50 μL total) were then carried out at 25° C. for 90 minutes.Reactions were terminated by the addition of 0.5% formic acid (finalconcentration), and a sample of each reaction was analyzed by SAMDITech, Inc. (Chicago, IL) using self-assembled monolayerdesorption/ionization time-of-flight mass spectrometry (Mrksich, M.(2008) Mass spectrometry of self-assembled monolayers: a new tool formolecular surface science. ACS Nano 2, 7-18).

Biochemical assay parameters are summarized in Table 3.

TABLE 3 Assay Assay Assay [Acetyl Reaction Construct/ [Enz] Peptide[Peptide] CoA] Time Enzyme amino acids (nM) substrate (μM) (μM) (min)KAT-5 Full length  9   H4 1-20 K5R K8R 1 0.5  90 K16R SGRGRGGRGLGKGGARRHRK(Biotin)-NH₂ KAT-6A 501-784 12.5 H4 1-26 K20Me1 1 1    90SGRGKGGKGLGKGG AKRHRK(Me1)VLRG GK(Biotin)-NH₂ KAT-7 Full length  6  H4 1-26 K20Me1 K5R 1 2   120 K8R K16R SGRGRGGRGLGKGG ARRHRK(Me)VLRGGK(Biotin)-NH2 KAT-8 Full length 12.5 H4 1-20 K5R K8R 1 5    90 K16RSGRGRGGRGLGKGG ARRHRK(Biotin)-NH₂

Enzyme Constructs

KAT5FL: Original protein before affinity tag cleavage:MHHHHHHSSGVDLGTENLYFQSNAMAEVGEIIEGCRLPVLRRNQDNEDEWPLAEILSVKDISGRKLFYVHYIDFNKRLDEWVTHERLDLKKIQFPKKEAKTPTKNGLPGSRPGSPEREVPASAQASGKTLPIPVQITLRFNLPKEREAIPGGEPDQPLSSSSCLQPNHRSTKRKVEVVSPATPVPSETAPASVFPQNGAARRAVAAQPGRKRKSNCLGTDEDSQDSSDGIPSAPRMTGSLVSDRSHDDIVTRMKNIECIELGRHRLKPWYFSPYPQELTTLPVLYLCEFCLKYGRSLKCLQRHLTKCDLRHPPGNEIYRKGTISFFEIDGRKNKSYSQNLCLLAKCFLDHKTLYYDTDPFLFYVMTEYDCKGFHIVGYFSKEKESTEDYNVACILTLPPYQRRGYGKLLIEFSYELSKVEGKTGTPEKPLSDLGLLSYRSYWSQTILEILMGLKSESGERPQITINEISEITSIKKEDVISTLQYLNLINYYKGQYILTLSEDIVDGHERAMLKRLLRIDSKCLHFTPKDWSKRGKWDYKDDDDKFinal protein after affinity tag cleavage:SNAMAEVGEIIEGCRLPVLRRNQDNEDEWPLAEILSVKDISGRKLFYVHYIDFNKRLDEWVTHERLDLKKIQFPKKEAKTPTKNGLPGSRPGSPEREVPASAQASGKTLPIPVQITLRFNLPKEREAIPGGEPDQPLSSSSCLQPNHRSTKRKVEVVSPATPVPSETAPASVFPQNGAARRAVAAQPGRKRKSNCLGTDEDSQDSSDGIPSAPRMTGSLVSDRSHDDIVTRMKNIECIELGRHRLKPWYFSPYPQELTTLPVLYLCEFCLKYGRSLKCLQRHLTKCDLRHPPGNEIYRKGTISFFEIDGRKNKSYSQNLCLLAKCFLDHKTLYYDTDPFLFYVMTEYDCKGFHIVGYFSKEKESTEDYNVACILTLPPYQRRGYGKLLIEFSYELSKVEGKTGTPEKPLSDLGLLSYRSYWSQTILEILMGLKSESGERPQITINEISEITSIKKEDVISTLQYLNLINYYKGQYILTLSEDIVDGHERAMLKRLLRIDSKCLHFTPKDWSKRGKWDYKDDDDK KAT6A 501-784:Original protein before affinity tag cleavage:MHHHHHHSSGVDLGTENLYFQSNAPPDPQVRCPSVIEFGKYEIHTWYSSPYPQEYSRLPKLYLCEFCLKYMKSRTILQQHMKKCGWFHPPANEIYRKNNISVFEVDGNVSTIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVLTQNDVKGCHLVGYFSKEKHCQQKYNVSCIMILPQYQRKGYGRFLIDFSYLLSKREGQAGSPEKPLSDLGRLSYMAYWKSVILECLYHQNDKQISIKKLSKLTGICPQDITSTLHHLRMLDFRSDQFVIIRREKLIQDHMAKLQLNLRPVDVDPECLRW TPVIVSNSFinal protein after affinity tag cleavage:SNAPPDPQVRCPSVIEFGKYEIHTWYSSPYPQEYSRLPKLYLCEFCLKYMKSRTILQQHMKKCGWFHPPANEIYRKNNISVFEVDGNVSTIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVLTQNDVKGCHLVGYFSKEKHCQQKYNVSCIMILPQYQRKGYGRFLIDFSYLLSKREGQAGSPEKPLSDLGRLSYMAYWKSVILECLYHQNDKQISIKKLSKLTGICPQDITSTLHHLRMLDFRSDQFVIIRREKLIQDHMAKLQLNLRPVDVDPECLRWTPVIVSNS KAT7: KAT7-1-611-FLAGOriginal protein before affinity tag cleavage:MHHHHHHSSGVDLGTENLYFQSNAMPRRKRNAGSSSDGTEDSDFSTDLEHTDSSESDGTSRRSARVTRSSARLSQSSQDSSPVRNLQSFGTEEPAYSTRRVTRSQQQPTPVTPKKYPLRQTRSSGSETEQVVDFSDRETKNTADHDESPPRTPTGNAPSSESDIDISSPNVSHDESIAKDMSLKDSGSDLSHRPKRRRFHESYNFNMKCPTPGCNSLGHLTGKHERHFSISGCPLYHNLSADECKVRAQSRDKQIEERMLSHRQDDNNRHATRHQAPTERQLRYKEKVAELRKKRNSGLSKEQKEKYMEHRQTYGNTREPLLENLTSEYDLDLFRRAQARASEDLEKLRLQGQITEGSNMIKTIAFGRYELDTWYHSPYPEEYARLGRLYMCEFCLKYMKSQTILRRHMAKCVWKHPPGDEIYRKGSISVFEVDGKKNKIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVMTEADNTGCHLIGYFSKEKNSFLNYNVSCILTMPQYMRQGYGKMLIDFSYLLSKVEEKVGSPERPLSDLGLISYRSYWKEVLLRYLHNFQGKEISIKEISQETAVNPVDIVSTLQALQMLKYWKGKHLVLKRQDLIDEWIAKEAKRSNSNKTMDPSCLKWTPPKGTDYKDDDDKFinal protein after affinity tag cleavage:SNAMPRRKRNAGSSSDGTEDSDFSTDLEHTDSSESDGTSRRSARVTRSSARLSQSSQDSSPVRNLQSFGTEEPAYSTRRVTRSQQQPTPVTPKKYPLRQTRSSGSETEQVVDFSDRETKNTADHDESPPRTPTGNAPSSESDIDISSPNVSHDESIAKDMSLKDSGSDLSHRPKRRRFHESYNFNMKCPTPGCNSLGHLTGKHERHFSISGCPLYHNLSADECKVRAQSRDKQIEERMLSHRQDDNNRHATRHQAPTERQLRYKEKVAELRKKRNSGLSKEQKEKYMEHRQTYGNTREPLLENLTSEYDLDLFRRAQARASEDLEKLRLQGQITEGSNMIKTIAFGRYELDTWYHSPYPEEYARLGRLYMCEFCLKYMKSQTILRRHMAKCVWKHPPGDEIYRKGSISVFEVDGKKNKIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVMTEADNTGCHLIGYFSKEKNSFLNYNVSCILTMPQYMRQGYGKMLIDFSYLLSKVEEKVGSPERPLSDLGLISYRSYWKEVLLRYLHNFQGKEISIKEISQETAVNPVDIVSTLQALQMLKYWKGKHLVLKRQDLIDEWIAKEAKRSNSNKTMDPSCLKWTPPKGTDYKDDDDK KAT-8: His-KAT-8-1-458-FLAGFinal protein (no cleavage): MHHHHHHMAAQGAAAAVAAGTSGVAGEGEPGPGENAAAEGTAPSPGRVSPPTPARGEPEVTVEIGETYLCRRPDSTWHSAEVIQSRVNDQEGREEFYVHYVGFNRRLDEWVDKNRLALTKTVKDAVQKNSEKYLSELAEQPERKITRNQKRKHDEINHVQKTYAEMDPTTAALEKEHEAITKVKYVDKIHIGNYEIDAWYFSPFPEDYGKQPKLWLCEYCLKYMKYEKSYRFHLGQCQWRQPPGKEIYRKSNISVYEVDGKDHKIYCQNLCLLAKLFLDHKTLYFDVEPFVFYILTEVDRQGAHIVGYFSKEKESPDGNNVACILTLPPYQRRGYGKFLIAFSYELSKLESTVGSPEKPLSDLGKLSYRSYWSWVLLEILRDFRGTLSIKDLSQMTSITQNDIISTLQSLNMVKYWKGQHVICVTPKLVEEHLKSAQYKKPPITVDSVCLKWAPPKHKQVKLSKKDYKDDDDK

-   -   underlined residues: His-TEV tag    -   italicized residues: Flag tag    -   underlined and italicized residues: His Tag

Table 4 shows the activity of selected compounds of this disclosure inKAT-5, KAT-6A, KAT-7, and KAT-8 inhibition assays. The compound numberscorrespond to the compound numbers above. Compounds having an activitydesignated as “A” provided an IC₅₀ of ≤10 μM; compounds having anactivity designated as “B” provided an IC₅₀ of 10.01-50 μM; compoundshaving an activity designated as “C” provided an IC₅₀ of 50.01-100 μM;and compounds having an activity designated as “D” provided an IC₅₀of >100 PM.

TABLE 4 KAT-5 KAT-6A KAT-7 KAT-8 Compound IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM)IC₅₀ (μM) I-1  A A A D I-2  A A A B I-3  A A A D I-4  A A A C I-5  A A AD I-6  B A B D I-7  B C A D I-8  D B B D I-9  B B A D I-10  A A A DI-11  C B C D I-12  C C A D I-13  A A A D I-14  C D B D I-15  B C A DI-16  B D A D I-17  A A A D I-18  A A A B I-19  D D B D I-20  A A A CI-21  A A A D I-22  D B A D I-23  A A A D I-24  A A A B I-25  B C A DI-26  A B A D I-27  B C A D I-28  B D A D I-29  B D C D I-30  D D D DI-31  A A A B I-32  A A A D I-33  B B A D I-34  A A B D I-35  A A A BI-36  B A A D I-37  C B B D I-38  A — A D I-39  B B C D I-40  D D D DI-41  B A C D I-42  D D A D I-43  B A C D I-44  C D D D I-45  D D C DI-46  B C A D I-47  A C D D I-48  A A A D I-49  D D D D I-50  A A B DI-51  A A A B I-52  B B A D I-53  A A A C I-54  C D D D I-55  A A A BI-56  B B A B I-57  B B A B I-58  D D D D I-59  B D D D I-60  D D D DI-61  D D B D I-62  B B A B I-63  A A A B I-64  A A A B I-65  C B A DI-66  A A A B I-67  B B B D I-68  A B B B I-69  B B A B I-70  B B B BI-71  B B A B I-72  B A A B I-73  A B A B I-74  B B B B I-75  A A A BI-76  B B A B I-77  B B B B I-78  A B A B I-79  B B A B I-80  B A B BI-81  A A B B I-82  A A A B I-83  B B A B I-84  A A A B I-85  A A A BI-86  A A A B I-87  B A B B I-88  A B A B I-89  B B A B I-90  B B B BI-91  A A A B I-92  A A A B I-93  B B A B I-94  A A A B I-95  B A A BI-96  A A A B I-97  A A A B I-98  A — A B I-99  A — A B I-100 B B B BI-101 A A A B I-102 A A A B I-103 B B A B I-104 A A A B I-105 A A A BI-106 A A A B I-107 A A A B I-108 B B A B I-109 A A A B I-110 A A A BI-111 A A A B I-112 A B A B I-113 B B A B I-114 A A A B I-115 A A A BI-116 A A A B I-117 A A A B I-118 A A A B I-119 B B B B I-120 B B A BI-121 B B A B I-122 B B A B I-123 B B A B I-124 A A A B I-125 B B A BI-126 A B A D I-127 A B A D I-128 B B A D I-129 A A A D I-130 A B A DI-131 B B A D I-132 A A A D I-133 D D A D I-134 B D A D I-135 A C B DI-136 D D D D I-137 B C B D I-138 B D C D I-139 B D A D I-140 B B A DI-141 A A A D I-142 A A A D I-143 C C C D I-144 D D A D I-145 D D B DI-146 B B B D I-147 D D D D I-148 B B B B I-149 B B A B I-150 B B A BI-151 C D B D I-152 B D D D I-153 D D D D I-154 B D A D I-155 D D B DI-156 B D A D I-157 A A A B I-158 A B A D I-159 A B A C I-160 B B A BI-161 A A A B I-162 A B A B I-163 A A A B I-164 B A A B I-165 B B B BI-166 A A A B I-167 B A A B I-168 B B A B I-169 B A A B I-170 B A A BI-171 A A A B I-172 A A A B I-173 A A A B I-174 A A A B I-175 A A A BI-176 A A A B I-177 A A A A I-178 B A A B I-179 A A A B I-180 A A A BI-181 A A A B I-182 A A A B I-183 A A A B I-184 A A A B I-185 B A A BI-186 A A A B I-187 A A A B I-188 B B A B I-189 A A A B I-190 A A A BI-191 A A A B I-192 B B A B I-193 B A A B I-194 A A A B I-195 A A A BI-196 A A A B I-197 A A A B I-198 A A A B I-199 A A A B I-200 A A A AI-201 A A A B I-202 A A A B I-203 A A A B I-204 B B A B I-205 A A A BI-206 A A A B I-207 B A A B I-208 B B A B I-209 A B A B I-210 A B A BI-211 A A A B I-212 B B A B I-213 A A A B I-214 A A A B I-215 A A A BI-216 A B A B I-217 A A A B I-218 A A A B I-219 A A A B I-220 B B A BI-221 A A A B I-222 A B A B I-223 B B B B I-224 B B A B I-225 A A A BI-226 A B A B I-227 A A A B I-228 A B A B I-229 A A A B I-230 A A A BI-231 A A A B I-232 B B B B I-233 B B A B I-234 A A A B I-235 A A A BI-236 A A A B I-237 B A A B I-238 A A A B I-239 A B A B I-240 A A A BI-241 A A A B I-242 A A A B I-243 A A A B I-244 A A A B I-245 A A A BI-246 A A A B I-247 A A A B I-248 A A A B I-249 A A A B I-250 A B A BI-251 B B A B I-252 A A A B I-253 B B A B I-254 A A A B I-255 B B A BI-256 A A A B I-257 B B B B I-258 A A A B I-259 A B — B I-260 A A A BI-261 B B B B I-262 A A A B I-263 B B — B I-264 A A A B I-265 A A A BI-266 A A A B I-267 A B A B I-268 A A — B I-269 A A — B I-270 A A — BI-271 B B — B I-272 A A — B I-273 A A — B I-274 A A — B I-275 A A — BI-276 A A — B I-277 A A — B I-278 A A — B I-279 A A — B I-280 B B A BI-281 A A A B I-282 A B A B I-283 B B A B I-284 B A A B I-285 A A A BI-286 A A A B I-287 A A A B I-288 A A A B I-289 A A A B I-290 A B A BI-291 A B A B I-292 A A A B I-293 A A A B I-294 A A A B I-295 A A A BI-296 A A A B I-297 B B A B I-298 A A A B I-299 A A A B I-300 A A A BI-301 B A A B I-302 A A A B I-303 A B A B I-304 A A A B I-305 B B A BI-306 A A A B I-307 B B B B I-308 A A A A I-309 A A A B I-310 A A A BI-311 A B A B I-312 A A A B I-313 A A A B I-314 B B A B I-315 A A A BI-316 A A A B I-317 A A A B I-318 A A A B I-319 A A A B I-320 A A A BI-321 A A A B I-322 A A A B I-323 A A A B I-324 A A A B I-325 A A A BI-326 A A A B I-327 A A A B I-328 B B A B I-329 A A A B I-330 A A A BI-331 A B A B I-332 A A A B I-333 A A A B I-334 A A A B I-335 A A A BI-336 A A A B I-337 B B A B I-338 A A A B I-339 B B A B I-340 A A A BI-341 A A A B I-342 A A A B I-343 A A A B I-344 A A A B I-345 A A A BI-346 A A A B I-347 A A A B I-348 A A A B I-349 B B A B I-350 A A A BI-351 B B B B I-352 A B A B I-353 A A A B I-354 A B A B I-355 A A A BI-356 A B A B I-357 A A A B I-358 A A A B I-359 A A A B I-360 A A A BI-361 B B A B I-362 B B A B I-363 A B A B I-364 B B A B I-365 A A A BI-366 A A A B I-367 A A A B I-368 A A A B I-369 A B A B I-370 B A A BI-371 A A A B I-372 A B A B I-373 B B B B I-374 A A A B I-375 A A A BI-376 A A A B I-377 B B A B I-378 A A A B I-379 B B A B I-380 A A A BI-381 B A A B I-382 B A A D I-383 A A A B I-384 A B A C I-385 A A A DI-386 A A A B I-387 A A A C I-388 A A A D I-389 A A A D I-390 A B — DI-391 A A — C I-392 A A — D I-393 A A — D I-394 B B — D I-395 B B — DI-396 A A — B I-397 — — — D I-421 — A — — I-422 — D — — I-423 — A — —I-424 — B — — I-425 — C — — I-426 — B — — I-427 — B — — I-428 — A — —I-429 — A — — I-430 — B — — I-431 — B — — I-432 — A — — I-434 — A — —I-435 — A — — I-436 — D — — I-437 — B — — I-438 — A — — I-439 — A — —I-440 — A — — I-441 — A — — I-442 — A — — I-443 — D — — I-444 — A — —I-445 — B — — I-446 — A — — I-447 — A — — I-448 — D — — I-449 — D — —I-450 — A — — I-451 — B — — I-452 — B — — I-453 — A — — I-454 — A — —I-455 — B — — I-456 — B — — I-457 — B — — I-458 — A — — I-459 — A — —I-460 — B — — I-461 — A — — I-462 B B — — I-463 — A — — I-464 — A — —I-465 — A — — I-466 — A — — I-467 A A A — I-468 A A — — I-469 D D — —I-470 D B — — I-471 A A A — I-472 D D — — I-473 A B A — I-474 A A A —I-475 D D C — I-476 A A A — I-477 A B — — I-478 A A A — I-479 A A A —I-480 B B A — I-481 A A A — I-482 B B A — I-483 A A A —

Table 5 shows the activity of selected compounds of this disclosure inKAT-5, KAT-6A, KAT-7, and KAT-8 inhibition assays. The compound numberscorrespond to the compound numbers above. Compounds having an activitydesignated as “A” provided an IC₅₀ of ≤10 μM; compounds having anactivity designated as “B” provided an IC₅₀ of 10.01-50 μM; compoundshaving an activity designated as “C” provided an IC₅₀ of 50.01-100 μM;compounds having an activity designated as “D” provided an IC₅₀ of >100μM; and compounds having an activity designated as “F” provided an IC₅₀of 1 μM.

TABLE 5 KAT-5 KAT-6A KAT-7 Compound IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) A-1  —B — A-2  — D — A-3  — D — A-4  — A — A-5  — B — A-6  — D — A-7  — D —A-8  — D — A-9  — D — A-10 — D — A-11 A A — A-12 B B A A-13 D D B A-14 DD B A-15 D D A A-16 A E E A-17 D B A A-18 D D — A-19 B C A A-20 D D BA-21 D D A A-22 B B E A-23 D D E A-24 C B A A-25 D D B A-26 D D D A-27 DD D A-28 E E E A-29 A E E A-30 A E A A-31 E E E A-32 D D B

Table 6 provides data for certain comparative compounds A-D, inparticular, the biochemical assay data for KAT-5, KAT-6A, KAT-7, andKAT-8 inhibition assays. Compounds having an activity designated as “A”provided an IC₅₀ of 10 μM; compounds having an activity designated as“B” provided an IC₅₀ 10.01-50 μM; compounds having an activitydesignated as “C” provided an IC₅₀ of 50.01-100 μM; and compounds havingan activity designated as “D” provided an IC₅₀ of >100 μM.

TABLE 6 Compound KAT-5 KAT-6A KAT-7 KAT-8 Name IC₅₀ (μM) IC₅₀ (μM) IC₅₀(μM) IC₅₀ (μM) A B B C D B A A A C C A A B D D B D D D

Cellular Assays

Inhibition of acetylation of H3K23 in Human cell line CAL-120. Cell lineCAL-120 was plated in eleven 10 cm tissue culture dishes at a celldensity of 4×10⁵ cells/cm² and treated with ten 2-fold serial dilutionsof compound A-30 starting at 10 μM and one dish with DMSO (vehiclecontrol) for 3 hours. Cells were tripsinized, washed twice with ice coldPBS and snap-frozen. Histones were extracted from cell pellets. Proteinconcentration was assessed and 60 ng of protein sample from histoneextraction was prepared in triplicate in 100 μl coating buffer (0.05%w/v BSA in PBS) and added directly to high binding 96 well plates.Plates were left at 4° C. overnight to allow protein to adhere. Coatingbuffer with histones was discarded and plates blotted, and 100 μL perwell of primary antibody solution of rabbit anti-H3K23ac antibody(Millipore 07-355) (1:600) and mouse anti-total H3 antibody (CST-14269)(1:500) in Odyssey buffer with 0.1% Tween 20 (v/v) was added to thewells of the plate and incubated for 1 hour. Plates were transferred toa Biotek plate washer and washed 3 times with 100 μL per well of washbuffer (1×PBS with 0.05% Tween 20 (v/v)). Next 100 μL per well ofsecondary antibody solution were added. The secondary antibody solutionconsisted of a 1:100 dilution of goat-Anti-rabbit IgG (H+L) Alexa Fluor680 (Life Technologies catalog A21076; Lot: 1655809) and 1:1000 dilutionof Donkey anti-mouse IgG (H+L) IRDye 800CW (Odyssey Catalog 926-32212)in Odyssey buffer with 0.1% Tween 20 (v/v) and incubated for 1 hour inthe dark at room temperature. The plates were washed 3 times with 100 μLper well wash buffer (1×PBS with 0.05% Tween 20 (v/v)) and then filledwith 100 μL per well of 1×PBS. Plates were imaged on the Licor Odysseyinstrument which measures integrated intensity at 680 nm and 800 nmwavelength. Both 680 nm and 800 nm channels were scanned.

Calculations were performed as follows:

First, the ratio for each well was determined by:

$\left( \frac{{anti} - {histone}H3K23{Acetyl}700{nm}{value}}{{anti} - {histone}{total}H3800{nm}{value}} \right)$

Then, the average of the ratio values for each test well was calculatedand used to determine the percent of H3K23Ac from vehicle for each testwell in the plate:

${{Percent}{of}H3K23Ac{from}{vehicle}} = \left( {\left( \frac{\left( {{Individual}{Test}{Sample}{Ratio}} \right)}{\left( {{Minimum}{Inhibition}{Ratio}} \right)} \right)*100} \right)$

Lastly, dose response curves were plotted as percent of control vs logof concentration, and relative IC₅₀ values were generated usingtriplicate wells per concentration of compound with the Graphpad Prismsoftware. FIG. 1 depicts a representative inhibition of acetylation ofH3 K23 cells by compound A-30 in the CAL-120 cell line.

Long term proliferation assay. A panel of multiple myeloma (MM) andacute myeloid leukemia (AML) cell lines were tested in 14-dayproliferation assays. Exponentially growing cells were plated, intriplicate, in 96-well plates at the appropriate cell density in a finalvolume of 150 μL. Cells were incubated in the presence of increasingconcentrations of compound A-30. Viable cell number was determined at 0,4, 7, 11, and 14 days using Calcein staining and using an Accumeninstrument to enumerate the number of cells. On days of cell counts,growth media and compound A-30 were replaced, and cells split back toinitial density. Total cell number is expressed as split-adjusted viablecells per well.

Calculations were performed as follows:First, the inhibition of proliferation was calculated for each well ateach treatment concentration at each timepoint with the followingformula:

${{Percent}{Inhibition}} = {100 - \left( {\left( \frac{\left( {{Individual}{Test}{Sample}{viable}{cells}{per}{well}} \right)}{\left( {{DMSO}{viable}{cells}{per}{well}} \right)} \right)*100} \right)}$

Then, for each cell line, concentration response curves were plotted asaverage and standard deviation from triplicate determinations as percentinhibition vs log of concentration of compound A-30. Absolute IC₅₀values (concentration of compound at which 50% inhibition occurs) weredetermined from the curve at at each timepoint using Graphpad Prismsoftware. Results for the 14-day timepoint are shown in Table 7. An IC₅₀value of ≤10 μM is designated as “A”; an IC₅₀ value of >10 μM isdesignated as “B”.

TABLE 7 Cell line Indication IC₅₀ (μM) KMS34 MM A RPMI8226 MM A NOMO1AML A OCIAML3 AML A KMS11 MM A LP1 MM A OCIAML2 AML B MOLM13 AML B SEMAML B THP1 AML B

EQUIVALENTS AND SCOPE

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents of theembodiments described herein. The scope of the present disclosure is notintended to be limited to the above description, but rather is as setforth in the appended claims.

Articles such as “a,” “an,” and “the” may mean one or more than oneunless indicated to the contrary or otherwise evident from the context.Claims or descriptions that include “or” between two or more members ofa group are considered satisfied if one, more than one, or all of thegroup members are present, unless indicated to the contrary or otherwiseevident from the context. The disclosure of a group that includes “or”between two or more group members provides embodiments in which exactlyone member of the group is present, embodiments in which more than onemembers of the group are present, and embodiments in which all of thegroup members are present. For purposes of brevity those embodimentshave not been individually spelled out herein, but it will be understoodthat each of these embodiments is provided herein and may bespecifically claimed or disclaimed.

It is to be understood that the disclosure encompasses all variations,combinations, and permutations in which one or more limitation, element,clause, or descriptive term, from one or more of the claims or from oneor more relevant portion of the description, is introduced into anotherclaim. For example, a claim that is dependent on another claim can bemodified to include one or more of the limitations found in any otherclaim that is dependent on the same base claim. Furthermore, where theclaims recite a composition, it is to be understood that methods ofmaking or using the composition according to any of the methods ofmaking or using disclosed herein or according to methods known in theart, if any, are included, unless otherwise indicated or unless it wouldbe evident to one of ordinary skill in the art that a contradiction orinconsistency would arise.

Where elements are presented as lists, e.g., in Markush group format, itis to be understood that every possible subgroup of the elements is alsodisclosed, and that any element or subgroup of elements can be removedfrom the group. It is also noted that the term “comprising” is intendedto be open and permits the inclusion of additional elements or steps. Itshould be understood that, in general, where an embodiment, product, ormethod is referred to as comprising particular elements, features, orsteps, embodiments, products, or methods that consist, or consistessentially of, such elements, features, or steps, are provided as well.For purposes of brevity those embodiments have not been individuallyspelled out herein, but it will be understood that each of theseembodiments is provided herein and may be specifically claimed ordisclaimed.

Where ranges are given, endpoints are included. Furthermore, it is to beunderstood that unless otherwise indicated or otherwise evident from thecontext and/or the understanding of one of ordinary skill in the art,values that are expressed as ranges can assume any specific value withinthe stated ranges in some embodiments, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.For purposes of brevity, the values in each range have not beenindividually spelled out herein, but it will be understood that each ofthese values is provided herein and may be specifically claimed ordisclaimed. It is also to be understood that unless otherwise indicatedor otherwise evident from the context and/or the understanding of one ofordinary skill in the art, values expressed as ranges can assume anysubrange within the given range, wherein the endpoints of the subrangeare expressed to the same degree of accuracy as the tenth of the unit ofthe lower limit of the range.

In addition, it is to be understood that any particular embodiment ofthe present disclosure may be explicitly excluded from any one or moreof the claims. Where ranges are given, any value within the range mayexplicitly be excluded from any one or more of the claims. Anyembodiment, element, feature, application, or aspect of the compositionsand/or methods of the disclosure, can be excluded from any one or moreclaims. For purposes of brevity, all of the embodiments in which one ormore elements, features, purposes, or aspects is excluded are not setforth explicitly herein.

All publications, patents, patent applications, publication, anddatabase entries (e.g., sequence database entries) mentioned herein,e.g., in the Background, Summary, Detailed Description, Examples, and/orReferences sections, are hereby incorporated by reference in theirentirety as if each individual publication, patent, patent application,publication, and database entry was specifically and individuallyincorporated herein by reference. In case of conflict, the presentapplication, including any definitions herein, will control.

We claim:
 1. A compound of formula I′:

or a pharmaceutically acceptable salt thereof, wherein: Z is selectedfrom —Cy, —(C₁₋₃ aliphatic)-Cy, or optionally substituted C₁₋₄aliphatic; Cy is an optionally substituted group selected from phenyl, a3-10 membered saturated or partially unsaturated carbocyclic ring, a6-10 membered bridged bicyclic carbocyclic ring, a 3-10 memberedsaturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur, a6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur, a 5-6 memberedheteroaryl ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an8-10 membered bicyclic heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen oxygen and sulfur; each of R¹ andR² is independently selected from halogen and C₁₋₄ aliphatic; R³ isselected from hydrogen, halogen, —CN, —NR₂, and optionally substitutedC₁₋₄ aliphatic; each R is independently selected from hydrogen,optionally substituted C₁₋₄ aliphatic, and —C(O)O(C₁₋₄ aliphatic); RingA is an optionally substituted 5- or 6-membered heteroaryl ring having1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;each R^(a) is selected from halogen and optionally substituted C₁₋₄aliphatic; and x is 0-3; provided that the compound is not


2. The compound of claim 1, wherein the compound is of formula I:

or a pharmaceutically acceptable salt thereof, wherein: Z is selectedfrom —Cy, —(C₁₋₃ aliphatic)-Cy or optionally substituted C₁₋₄ aliphatic;Cy is an optionally substituted group selected from phenyl, a 3-10membered saturated or partially unsaturated carbocyclic ring, a 3-10membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur, a6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur, and a 5-6membered heteroaryl ring having 1-3 heteroatoms independently selectedfrom nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring,and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen oxygen and sulfur; each of R¹ andR² is independently selected from halogen and C₁₋₄ aliphatic; Ring A isan optionally substituted 5- or 6-membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen and sulfur;each R^(a) is selected from halogen and optionally substituted C₁₋₄aliphatic; and x is 0-3; provided that the compound is not

3-8. (canceled)
 9. The compound of claim 1, wherein the compound is offormula I-a:

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1, wherein the compound is of formula II:

or a pharmaceutically acceptable salt thereof, wherein: Z is selectedfrom —Cy, —(C₁₋₃ aliphatic)-Cy or optionally substituted C₁₋₄ aliphatic;Cy is an optionally substituted group selected from phenyl, a 3-10membered saturated or partially unsaturated carbocyclic ring, a 3-10membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur, a6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur, and a 5-6membered heteroaryl ring having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring,and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen oxygen and sulfur; each of R¹ andR² is independently selected from halogen and C₁₋₄ aliphatic; R^(x) isoptionally substituted C₁₋₄ aliphatic; and each of R^(a) and R^(a′) isindependently selected from hydrogen, halogen and optionally substitutedC₁₋₄ aliphatic. 11-15. (canceled)
 16. The compound of claim 1, whereinthe compound is of formula II-a:

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim1, wherein the compound is of formula II-b:

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim1, wherein the compound is of formula II-c:

or a pharmaceutically acceptable salt thereof.
 19. The compound of claim1, wherein the compound is of formula III:

or a pharmaceutically acceptable salt thereof, wherein: Z is selectedfrom —Cy, —(C₁₋₃ aliphatic)-Cy or optionally substituted C₁₋₄ aliphatic;Cy is an optionally substituted group selected from phenyl, a 3-10membered saturated or partially unsaturated carbocyclic ring, a 3-10membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen and sulfur, a6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen and sulfur, and a 5-6membered heteroaryl ring having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring,and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatomsindependently selected from nitrogen oxygen and sulfur; each of R¹ andR² is independently selected from halogen and C₁₋₄ aliphatic; and R^(x)is optionally substituted C₁₋₄ aliphatic. 20-23. (canceled)
 24. Thecompound of claim 1, wherein the compound is of formula III-a:

or a pharmaceutically acceptable salt thereof. 25-29. (canceled)
 30. Thecompound of claim 1, wherein Z is —(C₁₋₃ aliphatic)-Cy. 31-32.(canceled)
 33. The compound of claim 1, wherein the compound is selectedfrom Table 1, or a pharmaceutically acceptable salt thereof.
 34. Thecompound of claim 1, wherein the compound is selected from Table 2, or apharmaceutically acceptable salt thereof.
 35. A composition comprising acompound of claim 1 and a pharmaceutically acceptable carrier orexcipient.
 36. The composition of claim 35, in combination with anadditional therapeutic agent.
 37. The composition of claim 36, whereinthe additional therapeutic agent is a cancer therapeutic agent.
 38. Amethod of inhibiting histone acetyltransferase activity of at least oneMYST family KAT, comprising administering a therapeutically effectiveamount of a compound of claim 1 to a biological sample or a patient.39-43. (canceled)
 44. A method of selectively inhibitingacetyltransferase activity of KAT-7 as compared to at least one ofKAT-5, KAT-6A, and KAT-8, comprising administering a therapeuticallyeffective amount of a compound of claim 1 a biological sample or apatient in need thereof.
 45. A method of treating a disease or disordercomprising administering a therapeutically effective amount of acompound of claim 1 to a patient. 46-51. (canceled)
 52. The method ofclaim 45, wherein the disease or disorder is cancer.
 53. A method oftreating a tumor comprising administering a therapeutically effectiveamount of a compound of claim 1 to a patient. 54-71. (canceled)